House's ketamine treatment has worn off and he is back to using his cane; but he doesn't want to talk about it despite everyone's concerns. House has to diagnose Dr. Ezra Powell, a 71-year-old renowned pioneer in the field of medical research who collapsed while studying cancer in lab rats. House puts Powell through diagnostic rigors, but the team is unable to come up with a conclusive diagnosis, and Powell's health continues to deteriorate. Becoming increasingly debilitated, Powell ultimately demands that the team stop the litany of medical tests and euthanize him. House strikes a deal with him and asks for one day to do tests on him.

The moral dilemma of whether to assist in his suicide and abide by Powell's wishes, or to ignore what their patient wants drives the team in very different directions. The team members have divergent opinions on the morality of helping Powell die. Cameron despises the idea of ignoring Powell's wishes and continuing the tests House orders, yet cannot bring herself to assist Powell in his suicide. Her inability to make up her mind is both central to the plot and to her character: throughout the episode the members of the team criticise her for her indecisiveness. Both Foreman and Cameron are opposed watching House put Powell to sleep, but Chase seems to have little problem. Wilson says that House has done it before "plenty of times" and House insists that it was only "to patients that [he] knew were terminal."

When House fails to diagnose Powell in one day, he visits him in his room to give him the lethal morphine dose. Foreman tries to stop him, but House persists and threatens him with "Someone is going to get a buttload of morphine, but I'm not exactly sure who at this point." Foreman and Cameron leave in shock and disgust, but Chase stays to assist. But instead of killing him, House puts Powell in a coma, so that he can do his diagnosis in peace. However, during a colonoscopy, Powell's lung gives out and House is forced to intervene by which he notices that Powell has lost reflex capabilities in his right arm. In order to proceed with additional diagnostic procedures, House wakes Powell from his coma and finds that Powell has also lost sensation in his abdomen and right leg. The conflict between Cameron's job and her indecision reaches a boiling point when House finally asks her to get a skin biopsy. Her refusal, saying they don't know whether it is necessary, prompts an outburst from him: "Exactly! You can’t decide if we’re helping or hurting him; if he’s good or bad; or if you want paper, plastic, or a burlap sack. Do your damn job." Cameron acquiesces, and has a conversation with Powell where he reveals that he feels things such as informed consent interfere with research and thus he does not let it stand in the way. Cameron slices a piece of skin off using his perspective as her solution, upon which Powell commends her for doing what she believes is right.

House ends up diagnosing Powell with amyloidosis using Congo red, inspired by the sight of a red thong worn by the teenaged daughter of a clinic patient (Ali, played by Leighton Meester), leading House to refer to her as "his muse." Chase also finds that it is of sub-type AA and therefore is a terminal illness. During the end scenes, Powell is seen struggling for breath in his hospital bed, and Cameron sitting nervously in the locker room. The following morning, Cuddy comes into House's office to let him know that Powell died at 2:30 am, although declared stable at 2:00 am. House denies any knowledge of it and asks Cuddy if she would want to know even if he did. House then goes to Cameron, who is crying at the hospital chapel, suggesting that she aided in the passing away of Ezra by euthanizing him. House tells Cameron that he is proud of her, and leaves.