A frantic Sam and Luka report diabetic Alex missing after he runs away to find his father. Acting on information from the police, they follow a lead to Iowa, then eventually head for Colorado. As they travel, they discuss their relationship, Sam tells Luka she doesn't want anymore kids. After finding Alex safe, Sam tells him the truth and takes him to see his father. In the ER, Susan, Pratt, and the nurses evaluate Ray, Neela, and Abby’s first days as R2s, while each of them struggle to manage patients, new interns, and their first attempts at teaching.

Ray attends to a surrogate mother who goes into labor prematurely after being involved in a car accident. A difficult decision must be made as the baby's life hangs in the balance. Pratt gets a visit from his estranged father Charlie. A depressed Kovač copes with another failed relationship when Sam announces she's moving out, but he gets emotional support from Abby, who joins forces with Neela to put a spoiled, rude patient in her place.

Luka has a bad day, while new nurse manager Eve Peyton causes a stir in the ER. Luka and Kerry treat a severely burned, nameless man. Luka’s treatment priorities for a woman in a skating accident and a boy with a head trauma result in a confrontation with Eve and a fight with the boy’s father. Abby helps a woman with the possibility of breast cancer, make a difficult decision and then makes a discovery about Dubenko. Eve changes Sam’s schedule as Sam and Luka have difficulty working together. At day’s end, Luka gets drunk at a bar and Abby gives him a ride home.

In the wake of heavy rains, the ER is flooded with diverse patients, including a baby involved in a suspicious car crash with her mother and a heart-attack victim visited by his sex therapist. Sam confronts Eve about her strict ways. Abby learns the details of Dubenko's condition and tactfully refuses his advances. Kovač protests when nursing home workers drop off Blaire Collins, who has been comatose for six years, for routine care, but later in the day, she unexpectedly regains consciousness.

Kovač bonds with Blaire, who has no memory of the carjacking and rape-murder incident that caused her coma, while her drug therapy becomes an issue. In the wake of Lewis' abrupt departure, new attending physician Victor Clemente arrives to help make the ER more efficient, but the residents are not too fond of him, despite his wide-ranging knowledge. Abby's breast cancer patient convinces her to take a long-delayed exam. Ray begins a sexual relationship with a young woman named Zoe Butler.

There’s monkey business in the ER as Clemente, Abby and Neela treat an infant chimpanzee. Ray discovers Zoe has chlamydia, and is underage. A recovering Dubenko trails the staff via a two-way television hook-up. A boy and his father are injured in a construction accident. Pratt reaches a decision about his relationship with his estranged father and learns the truth about his father's abandonment of him.

A kidnapped girl is used as a "human shield" by her kidnapper, and both are wounded during a shoot-out with police. While Abby treats the girl, she is caught in the middle of a dispute between Clemente and Luka over the girl's care. Neela assists Luka, then Dubenko, with the kidnapper. Later, Luka and Clemente argue over style and practice, leading Luka to put his name in as a candidate for Chief of Emergency Medicine. Abby takes her anger and frustration out on Luka, who responds by kissing her. Gallant’s leave is delayed, to Neela’s dismay, and Ray gets his comeuppance from Zoe’s father.

For Neela, what begins as a routine ride-along turns into a defining day when a commercial jet and a private plane crash over Chicago. As Clemente manages the trauma in the ER, Pratt joins Neela on-scene. Luka and Abby wake up together at Luka’s, but the crash soon takes them back to work, where the tension between Luka and Clemente continues. Sam recalls Haleh when extra nurses are needed, and earns Eve’s approval. As the day ends, Luka and Abby talk, and awkwardly decide to stay just friends while Neela has a welcome, and overdue, visitor.

Back from Iraq, Gallant surprises Neela by impulsively asking her to marry him. Kerry steps in to the Kovac/Clemente battle, encouraging them to get along, which results in a competition to be agreeable. Ray and a somewhat rusty Kerry treat a man with hypothermia, leading Morris to take a stand regarding the best course of action. Luka, Clemente and Sam treat a boy with HIV whose mother refuses to believe HIV causes AIDS. At the day’s end, Neela and Gallant are married, despite Neela’s doubts. At the reception, Luka and Abby celebrate his appointment as Chief of Emergency Medicine and realize they want more than just friendship.

It’s Christmas Eve in the ER, and Kovač arrives for his first day as Chief of Emergency Medicine wearing a Santa hat, with presents for everyone. Kerry, Pratt and Abby treat a girl who is the victim of a random bullet fired by gang members, leading to a vigil outside the ER and a "scared straight" lesson, administered by Pratt, in the consequences of gun violence. Clemente’s former flame arrives, and the fires re-ignite, despite his efforts to resist. When a testy Santa insults a group of blind children, Eve’s extreme response forces Luka to bring in the nursing supervisor, and Eve is fired. Haleh auditions singers for the Christmas party and finds a surprising partner in Morris. At the end of the day, the gang gathers for the annual Christmas party. Luka and Abby exchange gifts, and Abby tells Luka she's pregnant.

Abby and Kovač agonize over what to do about her unexpected pregnancy, with Abby eventually deciding to keep the baby despite her fears that it might be bipolar like her mother and brother. Neela and Kovač help a religious teenager weigh all her pregnancy options, but differ on what course she should take. Clemente's past is starting to catch up with him as police visit to investigate a missing person report on Jodie. Weaver falls on the ice and realizes she needs surgery.

With Luka eager to get home, Clemente AWOL and Kerry temporarily off her feet, Dubenko volunteers to cover the ER briefly, but quickly becomes overwhelmed. Abby’s excitement over her pregnancy means no sleep for Luka, and they head out for a bit of early shopping, and some dressing-room fun. Neela gets surgery as an elective, but is shocked to learn that rather that finishing his training in the US, Michael plans to return to Iraq. Ray helps Zoe escape to live with her sister when she arrives in the ER after a beating by her father, and Pratt fakes a blood test to help Darnell avoid arrest.

Dr. Nate Lennox, a former professor and mentor of Abby's, is brought into the ER in the last stages of ALS disease. In a series of flashbacks at County, the progression of his illness over the last six years is shown. He wants to give up, but Abby is determined to give him the strength to keep fighting.

An unexpected visitor -- Jodie's violent policeman husband Bobby, from whom she has filed for divorce -- puts Clemente in the middle of a domestic dispute that ends in Bobby shooting Jodie and Clemente. Kovač and Abby await important test results regarding their baby. Neela struggles with her surgical elective, and Ray tries to convince a homeless musician to accept help from his family. Jodie survives life-threatening surgery but is comatose, and her out-of-context remarks lead to Clemente being suspected in her shooting.

Carter works in the Sudanese desert, helping treat hundreds of diseased people including a woman raped by a militant group. Back in the ER, the police accuse Clemente of shooting Jodie. Pratt and Neela work to save a 14-year-old involved in a hit-and-run accident, but Pratt is infuriated when he discovers who hit the young teen. Kovač refuses to let Clemente return to work until he is reviewed by the Impaired Physician Committee. Jodie awakens from her coma and tells the police about her shooting, and Bobby threatens Clemente's life.

Weaver must make a difficult choice about having hip replacement surgery when the pain interferes with her work. Ultimately she decides to go forward with it, and asks Abby to take care of Henry if something goes wrong. When Abby discovers that one of her patients has contracted meningococcemia, the E.R. is briefly quarantined. Sam treats a man who collapsed, Richard Elliott, who offers her an intriguing job. Meanwhile, Neela decides to attend a support group for military spouses. Pratt confesses to Kovač that he falsified a blood test; an infuriated Kovač suspends him for five days.

Kovač, with Abby's help, works feverishly to save a young Turkish woman with multiple stab wounds. As the girls' condition worsens, Clemente steps in and decides to try a risky procedure; surprisingly, he and Kovac work together effectively for the first time, but unfortunately the patient goes beyond saving. Sam accepts a part-time job working for Richard Elliott. Neela pulls an all-nighter in preparation for a speech at a surgeon's convention but is disappointed when her speech goes awry, later reflecting on how close she and Ray have become.

A case involving two teens injured in a car accident proves baffling as the doctors try to determine why the girl is unconscious and why her male companion is so hostile toward the police, before Ray discovers he's deaf, and the cops jumped him. Neela copes with a visit from Gallant's bickering parents and Morris gets a tempting job offer from a pharmaceutical company. Olivia learns of Pratt's philandering. Kovač tells Abby that he is going to Darfur to help Carter, but when he realizes Abby is worried, he orders Pratt, who is just returning from suspension, to go. Sam enjoys the perks of working for Elliott. Ray struggles with some unresolved feelings for Neela as she decides to move back to Abby's apartment.

Pratt departs for Africa with attitude to spare but he quickly notices the scope of the horror there. Abby senses something is not what is seems when she treats a 12-year-old and her grandmother, then differs with Luka over the best course of action.Steve arrives at the ER complaining of a stomach pain. Clemente wants to release him but Neela thinks he needs to remain in the ER and is proven correct when Steve displays appendicitis. Morris and Dr. Albright argue about a patient, and Morris is proven correct. Clemente continues to be threaten by Jodie's ex husband.

Pratt gets to work in Darfur, but soon finds his eyes opened to the need all around him. Debbie attempts to persuade Dakarai to seek treatment for his illness. Carter, Pratt and Dakarai find themselves in the middle of the conflict when a man and his pregnant wife arrive at the camp needing treatment, with trouble not far behind. Events force Pratt and Dakarai to make a dangerous journey.

Gallant is killed in a roadside bombing in Iraq. Clemente's behavior spirals out of control along with his paranoia about Bobby, and Kovač is forced to take serious action when Clemente smashes a passing taxi outside the hospital and is diagnosed with PTSD. Dubenko offers Neela a surgical residency, but she and the rest of the staff then learn about Gallant's fate. Pratt readjusts to American medicine while treating a seriously injured family of two sons and their father and learning the cause of their injuries. Morris is offered a job with a major pharmaceutical company.

It’s a seemingly ordinary day with the usual collection of patients. But soon, the day becomes anything but ordinary as two prisoners intent on escape come to the ER for treatment, along with a hidden conspirator. Luka discovers them and is injected with a paralytic and they force Sam to become a tool in their plan. Soon, gunshots ring out, a staff member’s life is in jeopardy. The medical staff rush to the aid of the injured and Abby collapses just outside a trauma room where Luka is tied to a gurney.