Derek's wife, Addison, a surgical superstar from New York, is in Seattle to perform a fetal-heart operation. Derek isn't pleased to see her, and Meredith is feeling very betrayed. Meanwhile, Derek and Burke have some superstar surgery of their own to perform. Cristina has something to tell Burke and, as it happens, Burke has something to tell Cristina. And Webber appoints George to be his “eyes and ears” while he's recovering from surgery.
While Meredith and Cristina lick their wounds, they're kept busy in the extremely overbooked OR. Two of the cases stem from a car wreck caused by an alcoholic wife beater whose biggest advocate is his wife. Then there's a man with an obstructed bowel, who swears that he didn't ingest drugs. And a brain-dead woman whose organs are to be harvested is on the way. Meanwhile, George has something to tell the nurse who gave him syphilis. And Webber's wife (Loretta Devine) arrives to take him home.
The secret's out when Meredith's mother (Kate Burton) is hospitalized for diverticulitis. And Cristina's secret gets out when she collapses in agony while assisting Burke in surgery. Meanwhile, the Drs. Shepherd work together on the case of a heroin-addicted infant; a young woman who can't stop blushing arrives at the hospital; and George finally finds a way to wield power over Alex.
Addison (Kate Walsh) has divorce papers prepared; now all that she and Derek have to do is sign them. Meanwhile, Cristina, recovering from emergency surgery, proves to be an impossible patient, particularly when her mother is at her bedside. Speaking of mothers (and impossible patients), Ellis Grey (Kate Burton) keeps giving George fits. And Bailey's tough exterior cracks when a young man with cystic fibrosis---one of her first patients when she was an intern---returns to the hospital.
Lightning knocks out the power to the hospital, which leaves Alex and George stuck in an elevator with a patient---a police officer with a gunshot wound. The blackout also causes Cristina's patient, a man with a herniated disk, to lose access to his pain “medication,” i.e., porn videos. Meanwhile, Ellis, who's about to be discharged, keeps reliving her affair with Richard; and Meredith, who's assigned to work with Shepherd, gives him an ultimatum. Addison: Kate Walsh. Ellis: Kate Burton.
Meredith's long wait for “McDreamy” at Joe's bar is ended abruptly by a train wreck, which causes a rush hour in the ER. Cases include a young woman and a middle-aged man impaled---together---on a pole. They had been strangers but they bond quickly. Meanwhile, Cristina can't find an amputee's severed leg; Addison and Izzie try to save a badly burned pregnant woman's baby; and Alex treats a woman with an annoying friend.
As Derek and Addison see a therapist to try to put their marriage back together, Meredith and the other interns “steal” a psych patient who says he's pregnant. He isn't, but he isn't crazy, either. Meanwhile, Alex tries to talk a reluctant 18-year-old into an operation that could let her walk again; George has a heart-to-heart with the mousy husband of a bossy heart patient; and Cristina and Burke wrestle with whether to “come out” as a couple.
A young woman who was friendly with the Shepherds in New York arrives in Seattle and asks Addison to remove her uterus because she's at risk for cancer. But her husband objects because he wants children. And a hospital window washer survives a five-story fall (though the bird he landed on didn't), then begs George and Meredith to find his ex-girlfriend. Elsewhere, Meredith keeps running into Derek; Cristina gets dressed up for a date with Burke; and Bailey complains of being tired.
It's Thanksgiving and Izzie's cooking a turkey, but nobody's excited about it. Meredith sneaks off to the hospital (on a day off), where she and Derek treat a man in a persistent vegetative state---who wakes up. Cristina and Burke arrive for the feast, and Burke promptly takes over in the kitchen while Cristina finds an excuse to go work. And George is dragooned by his father and brothers to go on a turkey shoot.
The impending birth of quintuplets (and the surgeries on the newborns that are certain to follow) preoccupy the surgeons, but not completely: Burke gives Cristina a key to his apartment, but she's not overjoyed about it; Izzie and Alex are having an intimate “problem” (Alex is, anyhow); and a guy Meredith picks up at Joe's bar leaves her house the following morning with an intimate problem of a different sort.
The quints present a number of challenges, and so does their mother (Margaret Welsh), who's depressed. The sickest infant is assigned to Izzie, who's taught a painful lesson in doctoring from Addison. Izzie is also seething at Alex, who's depressed because of a medical mistake he made. Meanwhile, George uses leeches to treat an avid outdoorsman with skin cancer; and a prisoner (Rosanna Arquette) swallows four razor blades to get a “vacation” from prison.
It's Christmas, but nobody's feeling the spirit, except for Addison and Izzie---and Izzie's mad at Addison. A very pregnant Bailey needs a rest but has a very busy day instead, and George must cope with an ulcer patient's annoying family. As Cristina and Burke perform a heart transplant on a depressed 10-year-old, they discover that spirituality is one more thing they don't have in common. Plus, this might be Alex's last day at work. He has to retake his boards tomorrow, and he expects to fail.
The docs toast the New Year with a mandatory work limit, which Cristina finds constricting, and she complains about it to Bailey as they fly to harvest a heart for a patient with a crush on Izzie. Other patients include a frustrated novelist who has eaten his novel and a 14-year-old girl who hasn't reached puberty and yearns to be “normal.” Elsewhere, Addison detests Derek's trailer; Burke asks Cristina to move in with him; and Derek visits Ellis Grey (Kate Burton) without Meredith's knowledge.
Cristina is hesitant to “officially” move in with Burke, and George threatens to move out of Meredith's house unless she gets rid of Doc. Meanwhile, Alex gets his board-exam results; Meredith takes a blood test for Alzheimer's; and Bailey begins to have contractions. Patients include a competitive eater with hiccups; a rock guitarist who lost three fingers in an accident; a woman who's unnervingly cheerful; and an elderly woman who won't leave the hospital after being discharged.
As the docs muddle through a nurses' strike, Meredith makes a mistake treating an elderly patient, and it's caught by the patient's friends (June Lockhart, Betty Garrett and Rae Allen). Meanwhile, Izzie treats a pregnant teenager.
Christina Ricci guest stars in an episode in which a patient's arrival threatens the lives of everyone in the OR. There are also developments with Alex and Izzie. Dylan Young: Kyle Chandler.
While the WWII reenactor with the bomb lodged in his chest remains in Burke's OR, Bailey's injured husband remains in Derek's. Meanwhile, Bailey still hasn't delivered her baby. Hannah: Christina Ricci. Dylan Young: Kyle Chandler.
Derek and Addison are shaken by the arrival of someone from their past; Burke learns Cristina's secret; and Meredith delves into her family's dirty laundry after a visit with her mother. Dr. Mark Sloan: Eric Dane.
Meredith and George have a work dispute; new mom Bailey treats Addison for a gynecological problem; and Alex grows jealous as Izzie showers attention on heart patient Denny Duquette (Jeffrey Dean Morgan).
Cristina babysits for Bailey and doesn't take to it well at all; Addison and Derek come to terms with their relationship; and heart patient Denny Duquette (Jeffrey Dean Morgan) keeps coming between Alex and Izzie. Natalie Cole guest stars.
A rash of deaths at Seattle Grace brings out the doctors' superstitious sides, especially Izzie, who fears the worst about Denny's surgery. Meanwhile, Derek and Addison rethink their living arrangement, and Richard treats an old friend. Ollie: Mary Kay Place.
George overstays his welcome with Burke; Meredith learns a secret about her father; Bailey worries that her colleagues will treat her differently now that she's a mother; and Alex gets a lesson in bedside manners. Eileen: Mare Winningham. Finn Dandridge: Chris O'Donnell. Beatrice: Laurie Metcalf.
Izzie grills George about his personal life; Addison busts Alex about a sensitive case; and Burke treats his musical hero. Finn Dandridge: Chris O'Donnell. Callie: Sara Ramirez. Denny: Jeffrey Dean Morgan. Gwen Graber: Jayne Brook. Rose Ward: Jean Louisa Kelly.
Derek's mad at Meredith, and Burke's mad at Cristina. Meanwhile, Burke and Izzie make a new suggestion to a depressed Denny (Jeffrey Dean Morgan); and the doctors treat a family involved in an auto accident. They were hit by an overworked intern (John Cho) who had fallen asleep at the wheel. Betty Johnson: Frances Fisher. Finn: Chris O'Donnell. Callie: Sara Ramirez.
George works with Derek while Callie works with Meredith. Meanwhile, Finn (Chris O'Donnell) gives an update on Doc's health, and Burke and Izzie keep looking for a heart for Denny (Jeffrey Dean Morgan). Brad: Ken Marino. Will: Jesse Head. Deborah: Sydney Tamiia Poitier. Neal: Michael Arden. Doug Thomas: Michael Melhoan.
Denny's need for a new heart becomes critical; Cristina suddenly finds herself in charge in an ER; Richard has questions about a patient; Derek has a friend's life in his hands; Callie confronts George about his feelings for her; and Meredith and Derek come to a decision about Doc. Finn Dandridge: Chris O'Donnell.