Cristina returns from her “honeymoon” (with Meredith) and begins looking for Burke. At the hospital, new chief resident Callie welcomes a new batch of interns---including George, who is repeating his intern year, and Meredith's half sister Lexie (Chyler Leigh). Meanwhile, Richard resumes his post as chief of surgery, while Bailey tries to acclimate herself to her new duties at the hospital; Derek, at an impasse with Meredith, looks to fellow doctors for friendship.
The residents and interns treat the victims of an apartment-building explosion, while Alex investigates its cause; Mama Burke (Diahann Carroll) returns to collect her son's things while Cristina gets rid of her wedding presents; Lexie Grey (Chyler Leigh) tries to have a heart-to-heart with an unwilling Meredith; Callie is overwhelmed with her duties as chief resident while Bailey searches for an outlet for her pent-up leadership skills. Archie: Ben Vereen.
George's skill level at the hospital impresses the new interns, who don't know his "repeater" status. But life isn't as simple at home, where George feels he must tell Callie about his indiscretion with Izzie. Meanwhile, Meredith halfheartedly helps Lexie with her first emergency patient; and Mark and Richard attempt a radical new surgery to save a woman's ability to speak. Dr. Norman Shales: Edward Herrmann.
Adele Webber (Loretta Devine) rushes the niece who had her prom at Seattle Grace back to the hospital for treatment; Izzie reveals her feelings for George to a mutual friend, and the reaction is not what she expects; Derek shows Cristina how to be a better teaching resident; and Norman (Edward Herrmann), an intern who's considerably older than his colleagues, misdiagnoses one of Meredith's patients.
Halloween is a day of surprises (both good and bad) for the doctors of Seattle Grace: Alex receives an unexpected visit from Ava/Rebecca (Elizabeth Reaser); Meredith is convinced that her mother's ashes are haunting her; Cristina is snubbed by a surgeon she admires; and Callie announces George and Izzie's affair to their fellow doctors. Dr. Norman Shales: Edward Herrmann. Jack: David Clennon. James: Rocky Carroll. Olivia: Sarah Utterback.
With his wife filing for divorce, the Chief decides he needs to spend a “gentlemen's evening” with his fellow male surgeons; Cristina and Izzie heatedly compete for the same surgeries (and the favor of new cardiothoracic chief Erica Hahn); Meredith treats the survivor of a skydiving accident; the doctors treat two injured finalists in a bridal-gown promotional competition.
George and Izzie's romantic chemistry is put to the test; Derek asks for more than just sex from Meredith; Mark develops an unexpected crush on a fellow surgeon; and Callie's job as chief resident is jeopardized after she delegates many of her duties to Bailey.
The ER is filled with teenagers after a school-bus crash; Bailey treats a patient who was her high-school crush; Derek dates a fellow doctor; and Thatcher (Jeff Perry) sees Meredith for the first time since his second wife Susan's death.
Part 1 of 2. Meredith and the Chief struggle to save paramedics injured in an ambulance crash; Bailey treats a patient who refuses her help; Ava (Elizabeth Reaser) returns to see Alex---and meets his new girlfriend. Nick: Seth Green.
Conclusion. Meredith works furiously to save a paramedic trapped in an ambulance; Lexie literally holds the life of a patient (Seth Green) in her hands; Derek must rely on nurse Rose (Lauren Stamile) to save a patient when an OR computer breaks down; and Bailey keeps Tucker (Cress Williams) waiting while she operates on a white supremacist . Ava: Elizabeth Reaser.
While Bailey's family faces a medical trauma, the doc faces a marital one. Meanwhile, a surprise visit from George's mother (Debra Monk) comes as a shock to both Izzie and Callie; a faith healer challenges Erica and Alex's beliefs in Western medicine; and Derek must deal with the aftermath of his kiss with Rose (Lauren Stamile). Elizabeth: Glenne Headly.
Meredith, Alex, Izzie and Cristina compete in a surgical contest, with Bailey judging; George and his new roommate, Lexie, adjust to their squalid apartment; and Callie finds a friend in Erica Hahn. The episode takes place six weeks after Derek and Meredith ended their relationship and Derek began dating Rose (Lauren Stamile). Dr. Wyatt: Amy Madigan. Otis: Cheech Marin.
Addison (Kate Walsh) returns to Seattle Grace to perform a surgery and is surprised at the changes in her former coworkers' lives; Meredith and Derek's clinical trial has its first patient; Ava/Rebecca (Elizabeth Reaser) returns with news for Alex. Dr. Wyatt: Amy Madigan.
A "date-and-tell" policy is instituted at Seattle Grace after nurses complain about Mark's trysts, but Callie turns to him in a time of need. Meanwhile, Preston Burke's latest career accomplishments force Cristina to confront her feelings about him; and Derek and Meredith admit a military man into their clinical trial. Kevin: John M. Jackson. Adele: Loretta Devine. Dr. Wyatt: Amy Madigan. Rose: Lauren Stamile.
Dr. Wyatt won't let Meredith give up on therapy; the Chief is adamant about Erica performing a risky surgery on his mentor; Alex learns the truth about Rebecca's condition. Meanwhile, Cristina continues to act contrary to her nature, even cleaning her apartment, after receiving news of Burke.
In the fourth-season finale, the surgeons work as a team to free a young man from a block of quick-drying cement. Meanwhile, Meredith and Derek have one last chance at a positive outcome in their clinical trial; Izzie helps Alex care for a depressed Rebecca; Lexie finds out crucial info about George's status at Seattle Grace; and Cristina gets her mojo back after Meredith gives her the sparkle pager. Beth: Jurnee Smollett.