Напрежението между Адисън и Мередит расте. Завеждащият хирургията Ричард Уебър възлага на Джордж непосилна задача и назначава Бърк за свой временен заместник. Междувременно става ясно защо Дерек и Адисън са разделени. Бърк решава да постави работата си на първо място. Джордж успява да спаси бизнеса на всеобщия любимец Джо, собственик на бара срещу болницата.

Между Мередит и Адисън възниква напрежение. Бейли възлага на Джордж невъзможен случай, останалите стажанти оперират семейство, пострадало в катастрофа.

На Кристина ще й се наложи спешна операция, тъй като бременността ѝ ще се окаже извънматочна. Отношенията между Алекс и Изи стават все по-близки. Майката на Мередит е приета в болницата. Джордж получава трудна задача.

Кристина се оказва капризна пациентка. Майката на Мередит – доктор Елис Грей, изисква от болничния персонал постоянни грижи. На Адисън Шепърд ще ѝ се наложи да отложи напускането на болницата, заради пациент, болен от кистична фиброза.

Мередит и Дерек Шепърд трябва да убедят един вярващ човек, че дъщеря му се нуждае от животоспасяваща операция. Елис преживява за пореден път любовната си връзка с Ричард. Алекс и Джордж трябва да оперират в неподходящи условия, за да спасят живота на един полицай. Кристина се връща на работа и трябва да намери решение за пациента си, който губи достъпа до “болкоуспокояващото” си. Междувременно предстоят важни решения в любовния триъгълника Шепърд-Грей-Шепърд.

Мередит очаква решението на Дерек: дали той ще избере нея или ще остане при Адисън? Жертвите на тежка влакова катастрофа започват да прииждат, а Мередит е твърде пияна, за да асистира. Джордж е горд със сърдечната операция, която извършва в асансьора. Адисън предлага на Изи да я обучи на тънкостите в специалността си.

Кристина, Изи и Мередит се грижат за Шейн, психически болен пациент, който твърди, че е бременен. Дерек лекува момиче в инвалидна количка. Кристина и Бърк се двоумят дали да не съобщят за връзката си на всички. Докато Алекс се опитва да убеди пациентка, че операция ще спаси живота ѝ, тя настоява той да изясни отношенията си с Изи. Дерек и Адисън отиват на брачна консултация

В болница "Сиатъл Грейс" пристига семейна двойка - приятели на Дерек и Адисън. Съпругата решава да предприеме крайна мярка, за да не се разболее от рак като други жени от семейството. Кристина и Бърк излизат на първата си, не особено успешна среща. Завеждащият хирургията Ричард Уебър предлага на Бейли да му стане докторант.

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.

Dorie Russell is waiting for quintuplets, all 5 girls. Her husband seems more concerned than she is but she is set to bring her babies to their term of 36 weeks. All the departments are on call for the quintuplets as three of them have developped problems of different kinds. Meredith last night's stand shows up at the hospital with priapism and they need to call Derek Sheperd for a consult which puts Meredith in a very embarassing position. Alex and Derek must take care of a patient who has a tumor inducing thirst as a side effect. On the love side, Alex and Izzie are having some slight sexual problems, while Meredith goes on adding one night stands and Cristina is thrown off course by being "keyed."

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.

Cristina is bothered by a new year's mandatory work limit. Izzie patient, Denny Duquette, wants two things: 1. a heart transplant, 2. Izzie. Addison detests Derek's trailer, Derek visits Meredith's mom, George treats a young teen hermaphrodite frustrated by her pre-pubescence. Other news includes patients doing uncanny things and relationship havoc being wrecked between the doctors, as per usual.

Meredith and Cristina lie to each other and themselves about their relationships with McDreamy and Burke, respectively. George is given a hard task to expel a discharged and defiant woman from the hospital. Alex learns his fate after re-taking his medical exams. At the same time Izzie is trying to stop Alex from making stupid decisions when a patient that doesn't speak English is lied to by her coach. George, Cristina, and Alex compete in a hot dog eating competition.

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.

An explosive case arrives at the O.R. that might endanger all the lives of the people working there, which leads Dr. Burke to declare a "Code Black" for the hospital. Bailey worries where her husband is as she is in labor. Also Izzie and Alex may be creating some heat.

Derek is still operating when he finds out about Meredith's current situation. Meredith is freaking out about her situation. Webber and Bailey are dealing with medical health issues. Cristina and Izzie have their own issues to deal with because of Meredith's situation. Addison freaks out when George tries to find a solution to Bailey's impromtu postponement. Overall, Seattle Grace Hospital is still under code black and the situation is getting worse.

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 George are experiencing morning-after tension at home and at work and it has the rest of the doctors wondering what's up. Derek and Addison are experiencing their own version of morning-after tension as a result of Mark's visit to Seattle. Bailey, returning the favor that was done for her during the Code Black situation, must treat Addison for a specific feminine problem. Izzie and Alex are making headway in their relationship until Denny Duquette comes back. Soon Alex is not-so-oddly jealous of the attention Izzie is showing to Denny. Someone finds comfort in confiding in a patient who is going through an ordeal of his own. Burke deals with a patient and gets to observe the patient's unstable relationship with his fiancée.

The doctors are up to their necks in their usual levels of drama. Meredith is dealing with the backlash of sleeping with George, George and Burke are bonding in ways that bother and creep out Cristina, Cristina gets stuck on diaper duty, Bailey gets involved in a case even though she's still supposed to be on maternity leave, Addison and Derek have a talk, and Izzie is still flaking on Alex for Denny Duquette, the heart patient who didn't get a heart. In the patients-of-the-week department we've got a very pregnant woman, a hockey player who desires medically unnessasary amputation, and a woman with a fork in her neck who happens to be dying and has a struggling marriage.

After a series of deaths at the hospital some of the staff become very superstitious. Izzie worries about Denny and gets confronted by Alex. A patient with OCD drives Cristina crazy. Derek and Addison discuss their relationships with Meredith. Richard treats a friend from 17 years ago who reveals a secret about a dark time in his past that involves Ellis. George gets an earful about the women he's not talking to. Burke and Cristina argue about kicking George out.

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.

Addison's patient is a Catholic mother of seven. Addison gets in trouble after learning that the patient's husband won't use contraceptives. Derek treats a divorce attorney who asks if Derek is in need of her services. While Izzie and George are talking about their personal lives they "overhear" part of Derek's conversation with the divorce attorney who calls herself one of Seattle's best. Alex gets in trouble with Addison yet again for not being able to keep his mouth shut when other people think he should. A legendary jazz musician refuses to see medical reason. The musician is Burke's musical hero. Finn makes Meredith breakfast.

The staff attends to an intern from another hospital who has short-term memory loss. This intern, named Marshall, also has caused a car accident that involved a married couple, their unborn baby and the woman's parents who the staff are also treating. The pregnant woman is named Melanie and she will die but her baby may survive. One of the female interns meets up with a woman from her past who is planning on having a family of her own. Cristina is in a good mood although Alex, Izzie, George, and Meredith are having problems but in the meantime Burke hasn't forgiven Cristina for her late night faux pas. Meredith and Izzie are making fun of Callie's household habits and George and Callie are having a fight because of George's roommates. Addison is continuing to own Alex and he's upset about it. Denny has an outburst at Izzie and Derek has an outburst at Meredith.

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.

Denny needs a heart or else. Izzie and George go crazy trying to get him one. Derek has the life of a friend in his hands as he operates on Burke who has been shot. Burke cannot operate on Denny after Denny's heart stopped and now Denny is in a dire condition. Cristina gets put in charge of the ER and she is worried about Burke.

This episode is the second part of a two-hour season finale. Richard tries to get information from Addison about a family member's condition. Callie and George have a talk about his feelings. Meredith and Derek have a talk about Doc.