Picks up where the last episode left off. Meredith attempts to work with Addison Shepard. George is pimped out to relay the hospital gossip back to Webber. Meredith and Cristina relate at Emerald City Bar about what dating their respective attendings is like. Cristina ponders her relationship with Burke while trying to make a decision. Meredith is devastated by the latest blow to her love life. Meanwhile, Joe the bartender collapses.

As Cristina tries to recover, she proves to be a very difficult patient, and a visit from her mother doesn't improve her demeanor any. And Meredith's mother, Dr. Ellis Grey, has the hospital staff running in circles.

Cristina goes right back to working right after being discharged. Izzie isn't talking to Alex. Derek and Meredith treat a patient. George and Alex get stuck in an elevator.

Train Wreck victims come to Seattle Grace and all staff gets called in. Everyone deals with really weird cases. Except Addison and Izzie. They work with a woman who is pregnant.

Cristina, Izzie and Meredith take care of Shane, a man who appears to be crazy and claims that he is pregnant. Shane's case induces a spreading fascination among the staff. George relates to a patient's husband.

It's Thanksgiving at Seattle Grace Hospital but the holiday's festivites are less than in order. Meredith and Derek try to counsel a family after their relative has had a seriously traumatic accident.

The holiday season has started but not everyone is in a festive mood. This is Alex's last day in the hospital unless he passes his boards practical exam the next day, thus everyone helps him to review so that he succeeds. However, Izzie is not happy about the others helping him and Meredith has to remind her of the true spirit of the Christmas holiday. Justin is in need of a new heart. One is available but he does not want it because he does not believe Santa gave it to him as his mother said. Cristina and Burke, both handling Justin's case, have opposing views on the matter due to their different stances on religion. Despite a reconciliation with his wife, Derek isn't in a festive mood. George has a simple case of a woman who has a bleeding ulcer, he realizes that the ulcer is caused by her entourage but fails to keep them away, with the consequence that it perforates.

All the nurses at Seattle Grace Hospital go on strike, leaving the doctors to fend for themselves. George refuses to cross the picket line and finally joins the nurses on their strike while Alex, Cristina, Izzie and Meredith meets Bailey's stand-in: Dr. Cindy Aaron, the complete opposite of Miranda Bailey. Izzie agrees to work on a difficult pregnancy case with Addison, while Cristina and Alex are in the pit attending to a young married woman with a real bad case of rash. Meredith happens on an old woman that she needs to intubate and then learns she was DNR.

Derek and Addison's relationship is rocked to the core when a former friend comes to Seattle Grace and his presence promises to shake things up for a few members of the staff. Burke and Cristina's relationship is affected when one of her secrets is outted. Alex and Izzie are having similar reactions to their closet scenes during the Code Black crisis. On top of this a cocky doctor shows up to piss Derek off in all kinds of ways. A patient is suffering from constant orgasms and her condition sparks interesting conversations among the staff. George is trying to figure out how to get Meredith to see him as more than just a housemate. Another patient, that Derek is treating, is dealing with a rare disorder and needs his parents support and understanding. Burke has a patient who inspires him to talk to Meredith and Cristina about doing what they say they will. Meanwhile, Meredith learns more about her family (in fact maybe more than she may have wanted to know) through her parents.

Meredith and Izzie take up knitting. Derek operates on Andrew, a spelling bee champ with a serious head injury. Bailey gets in on Andrew's surgery because she's worried that her coworkers won't recognize her Nazi-status now that she's a mother. Addison's patient has an unborn baby with medical issues. After Alex fails to bite his tongue when a terminal patient routinely lies to her daughter about her health he gets a lesson in bedside manners from Burke. George also begins to overstay his welcome at Burke's apartment after Callie visits him. Meredith has more confusing and uncomfortable encounters with members of her family. One of the female doctors meets a veterinarian named Finn. Izzie flirts with Denny and they play more naughty-Scrabble. Meredith, Derek, and Addison sarcastically take another small stab at their friendships.

George and Derek work together, Denny still doesn't have a heart, and Meredith gets paired with Callie. A 12-week pregnant girl dies in the O.R. and her parents try to keep the baby alive. This causes tension between Derek and Addison. One doctor's overreaction unites two bickering patients. Finn is still treating Doc for medical problems.

Meredith must make an important choice about which path she wants to follow to determine the future of her love life. While she considers her future she and others have flashbacks of their pasts. Cristina spends time with Burke while he recovers. Webber and Adele have a conversation after he spends the night at the hospital. Everyone attempts to deal with Izzie's choice to quit. George seeks relationship advice from Derek.

Cristina meets Burke's parents, the interns try to get Izzie's job back, and Addison takes a day off, a surgical patient may be living her last day. Some of the interns want to know why Bailey won't talk to Izzie. Meredith tries to decide between Derek and Finn and comes to a decision somewhat. Webber finds out that Callie has been living in the hospital and he confronts her about it.

Shawn Sullivan, a car salesman who just had surgery, wants to get back to his routine so he doesn't lose his renown. Addison works with a pregnant woman named Rebecca who may need a C-section and Addison doubts her medical skills. Rebecca wants to have the baby naturally. Derek and Mark's opinions clash when the try to decide the course of treatment for a burn victim. Izzie gets surprised. Cristina pushes Burke to get better faster.

The men of Seattle Grace go on a camping trip together, Addison and Callie must team up to work on a patient, Meredith assists Sloan with a procedure unlike any she has experienced, and, suspicious of her recent actions at the hospital, Bailey confronts Cristina. A 9-year-old is seen by Cristina after he swallowed Monopoly game pieces. A pregnant 25-year-old, is brought in after she slipped in the shower. She doesn't want medicine to take away the pain from her injury so not to put her baby's growth in jeopardy. Doctors take care of Daniel, a man who wants a sexual reassignment surgery and who now goes under the name Donna. Accompanying Daniel is his wife of the past 10 years, who was surprised to see him want that surgery but, after much struggling, decided to stay by his side.

George's father has a serious heart problem that requires surgery and George chooses Burke to do the procedure. Burke doubts himself because he knows the pressure this kind of surgery will put on him, but Cristina believes the team can handle it. Derek works with Meredith on being a couple again and tries work with Addison on more civil terms. A patient has had mutiple plastic surgeries so that his girlfriend will like him more. A mom wants her daughter's babysitter fired, after she is brought in with multiple injuries, but the girl likes the babysitter more than her mother.

Cristina and Burke continue to play Uncle until one of them gives in. Derek and Meredith are fighting over the reason for their sleepless nights. Meredith tries to talk to her father about his side of the story. There's tension between Alex and Addison. There is even more tension between Addison and Mark. Addison confides in Callie. Bailey wishes she didn't have to keep a secret from one of the interns. Callie rushes to be with George after she learns that his dad needs an emergency procedure. Izzie may have found 'some good to do' with her inheritance.

Everyone is pushing for Meredith to survive, or in this case to be revived. People are still dealing with the fallout from the ferry disaster. A young man named Lucas is having problems with brain-mouth coordination. Someone else dies.

Colin Marlow continues to try to get in the way of Cristina and Burke's relationship. The daughter that Izzie gave up for adoption needs something from her. This episode features a pro chess player, a flirtatious woman, and a mother named Mrs. Malone. Mr. and Mrs. Malone haven't talked to their daugther in a while because of their son-in-law. Someone goes to see a priest.

The interns finally take their first year medical exams, the biggest test of their careers, and one of them is ill-prepared. Callie grows more suspicious of George and Izzie. The doctors treat a patient named Dale. Three mountain climbers are treated. Cristina works on her vows. Adele wants Addison to keep a secret from Richard.

The mountain climbers lie about the axe in their friend's head, telling Derek that it accidentally got there. During surgery, he and George discover that it was deliberately put there, and one of the climbers admit that he was trying to "put him out of his misery". Adele is saved after Richard finds her lying in the bathroom and is stabilized, but soon suffers a miscarriage. Richard learns Adele was actually pregnant with his son, not someone she had one night stand with. Bailey is disappointed to see that Callie is the new Chief Resident and begins to question her abilities as a surgeon. Richard chooses Derek as Chief of Surgery, but he refuses, telling him that he isn't done doing what he does best. Cristina and Burke's wedding day arrives, but Cristina won't stay out of the hospital. However, Cristina's nervousness results in Burke's realizing that he does not love the real Cristina and leaves her. Meredith and Derek are uncertain about their future and despite Derek admitting that she is the love of his life, they call their relationship over.

Meredith is sent into a state of panic when Derek finds her mother's diary in the house. Meanwhile, Callie stresses while preparing for her first date with Erica. Later, Cristina stumbles across a part of the hospital no one has ever seen before.

Bailey heads up a "domino procedure" in which each surgery hinges on the one preceding it. Meanwhile, Derek gets sole credit for the brain-tumor study he did with Meredith; Lexie tries to get George to notice her romantically; and Sloan counsels a desperate Callie in the ways of love.

Bailey teams with Seattle Grace's new pediatric surgeon, Dr. Arizona Robbins, to save the life of a young patient near and dear to her heart, as the admittance of a death row inmate at the hospital stirs anger in Derek and further erodes Meredith and Cristina's friendship; meanwhile, Callie and Sloan work as a team to fight their respective attractions to Sadie and Lexie, and Izzie tells Alex that she's seeing Denny.

Addison, Naomi and Sam rush the ailing Archer to Seattle Grace and reunite with old friends Derek and Mark to help save his life; meanwhile, Izzie employs her fellow doctors in a medical game designed to help teach the interns, and Owen runs into a significant someone from his past

Owen recruits Dr. Teddy Altman, a former Iraqi veteran, as the new cardiothoracic surgeon. Cristina questions her abilities in the E.R. and relationship with Owen. Izzie returns to Seattle Grace with her high school mentor seeking treatment for his dementia. Richard's responsibilities, post-merger, are taking a toll on him.

As Thanksgiving, Christmas and New Year's pass, Miranda gets a visit from her father, William who disapproves of her choices in life. Mark and Lexie cope with an arrival of a woman from his past. Thatcher questions the Chief's recent behavior as Meredith comes to his defense.

In his new role as Chief, Derek restores the hospital lecture series, and Richard, Bailey and Callie present to the group pivotal surgical cases from their pasts Bailey reflects on her first days as a shy resident, Callie looks back on a polio case, and Richard recalls a case in which he and Ellis worked on a patient diagnosed with GRID, a virus later called AIDS.

The residents are on their own with the dreaded night shifts while the attendings go out to play to celebrate Derek's grant for his clinical trial.