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.

Meredith discovers that Derek has a problem sleeping while her father comes to visit the hospital. George's father is moving from one surgery to another. A patient named Heather checks into the hospital. Heather is 17 and has a nasty attitude that results from her medical condition and all the surgeries it has required her to have. Izzie has an emotional breakdown when she tries to hand over something very important to her. George's family comes to visit to celebrate his father's surgery. Cristina and Burke are playing Uncle.

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.

The race between the attending physicians for the Chief of Surgery position heats up after a new competitor enters the fray. They soon realize that the new surgeon, Colin Marlow, was Cristina's professor in medical school and they used to have a long-term relationship. He begins to lie to Burke in order to protect her secret, but is soon faced with the realization that their relationship is on the rocks. George finds out that Callie's family is rich, but she had previously hidden the fact in order to find out whether George loves her for who she really is. Derek treats his former colleague from New York, and forces her to have surgery for brain cancer in order to save her future, no matter what the post-surgery risks are. Alex continues to work with Jane Doe, whose memory doesn't seem to come back. He moves in with Meredith and they have a dinner with her father and stepmother. She seems to connect with Susan, but her relationship with Thatcher seems to be irreparable. Izzie wakes up, realizing that she has slept with George while they were both drunk.

Meredith works on her relationship with Susan and Thatcher. Cristina has to deal with her mother and Burke's. Alex continues to tend to Jane Doe/Ava. Meredith and Derek's relationship has a problem that needs resolution quick. Addison sees her god-daughter which leads to a job offer outside of Seattle. Derek has to perform surgery. Burke has a reservation about marrying Cristina. Many new people guest star in the course of Addison's road trip to California. Addison considers moving to be closer to her old med school friends until she discovers that drama she wishes to leave behind isn't exclusive to Seattle. Her friends who she thought had it all, are divorced. A pregnant woman must discover who the father of her child is.

Meredith works on her relationship with Susan and Thatcher. Cristina has to deal with her mother and Burke's. Alex continues to tend to Jane Doe/Ava. Meredith and Derek's relationship has a problem that needs resolution quick. Addison sees her god-daughter which leads to a job offer outside of Seattle. Derek has to perform surgery. Burke has a reservation about marrying Cristina. Many new people guest star in the course of Addison's road trip to California. Addison considers moving to be closer to her old med school friends until she discovers that drama she wishes to leave behind isn't exclusive to Seattle. Her friends who she thought had it all, are divorced. A pregnant woman must discover who the father of her child is.

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.

Izzie and George's new-founded relationship results in them having bad sex. Callie's Chief Resident position is taken away from her, and Bailey is the humble replacement. Meredith can barely handle it with Lexie anymore.

There has been a bus crash and the patients are in the ER. Meredith and Derek's relationship gets more complicated when he dates a fellow doctor. Meredith's dad goes to visit her at the hospital.

As preparations continue for Meredith and Derek's wedding, Izzie receives a surprise hospital visit from her handful-of-a-mother, Robbie. Meanwhile, a newly sober Thatcher visits his daughters, Meredith and Lexie, in order to make amends, and the Chief and Meredith bitterly fight over a controversial medical case.

When Meredith and Lexie's father, Thatcher, returns to the hospital with a failed liver, it's up to Meredith to save his life. Meanwhile, Izzie empathizes with a patient riddled with tumors, as Mark, annoyed with Cristina's competitive zeal, tricks her into assisting on an unusual surgery.

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.

Thatcher Grey, Meredith and Lexie's father, returns to Seattle Grace with stomach pains and a new, twenty-something tattooed girlfriend, Danielle. Meanwhile, Alex clashes with the new OB, Dr. Lucy Fields, over a patient and Mark places Jackson on his service in exchange for information on Lexie.

Amelia and Koracick tackle a daunting surgery on Catherine while Richard and Jackson hope for the best. Meanwhile, Richard urges Meredith to visit her father, Thatcher, before his time is up.