Amidst a series of intense treatments, Izzie throws herself into Derek and Meredith's wedding plans, but the stress of her illness takes its toll on Alex - who freezes during surgery just as George begins to excel. Meanwhile: Callie's father arrives at Seattle Grace, but is less than pleased to meet his daughter's girlfriend; Owen seeks help to quell his PTSD outburtsts.
All eyes are on Derek as he is set to perform his first surgery after his breakdown; attention is also set on Izzie, whose medical condition requires her to undergo a difficult surgery; and Owen has another PTSD episode that injures Cristina and traumatizes both of them, throwing the future of their relationship into question.
After his fellow surgeons try and fail to bring Derek back to work, Meredith must summon the strength to convince him. Meanwhile the hospital is abuzz as Mark attempts a rare face transplant surgery. Cristina, at last awarded her first solo surgery, is more focused on the needs of her friends, and Izzie does her best to keep her medical condition a secret.
After learning at a deposition that more of his patients have died than survived, Derek decides to quit, even as Meredith refuses to give up on him. Meanwhile Bailey and the Chief continue to bicker over her peds fellowship until Adele steps in to mediate. The interns discover something unsettling on a "patient x," unaware that the charts they're looking at are actually Izzie's.
Derek's confidence is shaken like never before as he faces off with Addison over what course is best for their dying pregnant patient; Cristina calls the abilities of a renown surgeon into question after she botches a standard procedure; and Bailey, who has decided to pursue a fellowship in Pediatrics, is appalled by the Chief's less-than-stellar recommendation letter.
In a "Private Practice" crossover episode, Addison, Naomi and Sam rush Addison's ailing brother, Archer (Grant Show), to Seattle Grace in an effort to save his life. Meanwhile, Owen runs into a significant someone from his past; and Izzie employs her fellow doctors in a medical game designed to help teach the interns.
Now that Derek has the engagement ring, he searches for the perfect way to propose to Meredith, as Lexie demands that Mark go public with their relationship, and Bailey, encouraged by her work on recent cases and by Dr. Dixon, considers a new direction for her medical career.
Bailey grows desperate as a patient's condition becomes more and more dire. Everyone in the hospital is stepping up to try to find the boy a new organ donor, including Meredith, who considers a death row patient's wish to die before execution. Meanwhile, an injury leaves Mark in a compromising position in the OR and Cristina awkwardly avoids Owen.
Derek's mother, Carolyn, makes a surprise visit to Seattle and meets Meredith for the first time, as Mark tries to conceal his relationship with Lexie from her as well; meanwhile, death row inmate William wishes to donate his organs to Bailey and Arizona's patient, as Owen and Cristina try to go on their first date.
While Bailey teams with new pediatric surgeon Arizona Robbins (Jessica Capshaw ) to save a young patient near and dear to her heart, the arrival of a death-row inmate at the hospital angers Derek and further erodes Meredith and Cristina's friendship. Meanwhile, Callie and Sloan join forces to fight their respective attractions to Sadie and Lexie; and Izzie tells Alex that she has been seeing Denny (Jeffrey Dean Morgan). William: Eric Stoltz. Melinda: Samantha Mathis.