Aboard the TARDIS, the Doctor prepares to depart as Rose says goodbye to Mickey and Jackie. They leave and the Doctor warns they'll be going further than they ever have before. They materialize in a galaxy in the distant future where they're on New Earth. As they explore, they're unaware that a robot drone has seen them and identified Rose as a pure-blood human. A female voice monitoring them says that she recognizes Rose, while the Doctor notes he has a summons on his psychic paper asking him to come to Ward 26.. It becomes clear that Cassandra is the one monitoring them with the aid of her assistant, Chip.
Rose and the Doctor make their way to New New York and the hospital. They're separate when Chip cuts them off in separate elevators and redirects them to different locations as they undergo Level 1 Disinfection Rose is in the basement where Chip greets her, while the Doctor talks to one of the Cat Nurses, Sister Jatt, in Ward 26. The Doctor notes that one patient, the Duke of Manhattan, is suffering from Pentrifold Regression and will soon die of an incurable disease. He then notices the Face of Boe, and is told by Sister Jatt that the Face is dying of old age after thousands of years.
In the basement, Rose finds a projector showing a film of a party and a young attractive woman. She recognizes the woman as Cassandra, who is waiting behind her with Chip. Cassandra explains Chip's a force-grown clone and that her brain survived and her eyes salvaged. She is in hiding and Chip has stolen medicine to keep her alive. Cassandra reveals she has found out secrets about the hospital and the Nurses. She then traps Rose and has Chip activate the Psychograph. Cassandra's mental pattern is transferred into Rose and vice versa.
Novice Hame talks to the Doctor about the Face of Boe, and how there's a prophecy that before he dies, the Face will tell a great secret to another wanderer, the man without a home, the lonely god.
Cassandra-in-Rose reads Rose's mind and realizes the Doctor has changed faces. The Doctor calls her and Cassandra-in-Rose covers as best she can. Then the Duke of Manhattan asks the Doctor over and notes that he's been cured, much to the Doctor's surprise as his cure hasn't been discovered yet. Matron Casp comes over and deflects the Doctor's concerns, then secretly orders that the Duke must be disposed of.
Cassandra-in-Rose hides a bottle of perfume in her bosom then goes to check out the Nurses. Matron Casp and Sister Jatt go down to a series of pods and examine one of the people inside, who begs for help, and they destroy the individual inside.
The Doctor meets with Cassandra-in-Rose and talks about the Nurses' amazing series of cures. The Doctor asks about her odd lapses and Cassandra-in-Rose kisses him in response before they look for an information terminal. They discover there's a missing level and gain access to it, unaware that Novice Hame is following them. They find a huge room filled with millions of pods, and open one to find a human covered in boils. The Doctor realizes each pod holds an individual who has been infected with every known disease in the galaxy. He explains that they were born sick as a way for the Nurses to find their cures. Novice Hame approaches them and explains that the subjects are not real people and they are finding cures for many more humans. The Doctor demands to know what they've done with Rose, realizing she would be far more upset at what is happening. In response Cassandra-in-Rose drugs him with her "perfume" and then raises the alarm. She locks the Doctor in a pod and warns that he'll be infected in three minutes when the cycle kicks in. Cassandra-in-Rose leaves him as Casp and Jatt confront her, and she demands payment in return for keeping her silence. They refuse and Cassandra-in-Rose tells Chip to open all the pods, including the Doctor's. All of the highly contagious subjects advance on Casp and Jatt, then destroy the sealing mechanism. More of the subjects emerge as the Doctor and the others run away. The subjects touch Sister Jatt, killing her instantly with disease.
The plague subjects get into the hospital proper and begin infecting the visitors, while Chip is cut off from Cassandra-in-Rose and the Doctor. Chip jumps down a waste chute then locks himself in a pod to protect himself. Trapped in Cassandra's lair, the Doctor tells Cassandra-in-Rose to leave Rose and threatens her with the sonic screwdriver. Cassandra responds by jumping into the Doctor's body, freeing Rose. Now Cassandra-in-Doctor checks out "her" new body before the plague subjects break in and they flee up a lift shaft. In the upper levels, the remaining patients lock themselves in to avoid contagion but their time is running out.
In the lift shaft, Matron Casp grabs Rose and tries to pull her down, but the plague victims grab her first and Casp dies a hideous death as she falls down the staff. They get to the top but Cassandra-in-Doctor doesn't know how to use a sonic screwdriver to get them past the locked door so Cassandra jumps back into Rose. The Doctor orders her back to return to his body and she finally jumps into one of the plague victims. The Doctor opens the door and Cassandra manages to jump back into Rose as they escape. Cassandra is shocked by her brief impression of the plague victim's thoughts and how she had never been touched.
The Doctor and Cassandra-in-Rose emerge into the upper level where the remaining uninfected visitors try to override the quarantine and escape. Rather than break quarantine, the Doctor straps on all of the cures the Nurses have developed. He goes back down the elevator shaft and Cassandra-in-Rose is forced to go with him when the plague subjects advance. He lands on top of an elevator and dumps the solution into the disinfection system, then calls them into the elevator. They are cured and in turn touch the others, spreading the cure. He tells Cassandra-in-Rose that together they've created a new race of beings and she can't deny them.
The NYPD take the remaining Nurses into custody. The Doctor goes to talk to the Face of Boe, which has recovered. The Doctor asks about the great secret, but the Face says they shall meet one final time and he will tell the secret then, before teleporting away. He then tells Cassandra-in-Rose that she's lived long enough and it's time to leave. Chip arrives, having survived, and Cassandra-in-Rose realizes she has a willing body to move in to. Cassandra moves into Chip's body over the Doctor's objections, but realizes that Chip's cloned body will soon expire. She refuses the Doctor's offer to help her and accepts there's no place for her any more. The Doctor does offer her one last thing: he takes her in the TARDIS to the party from the movie projector and lets her see her body in its original form. Cassandra-in-Chip approaches her original self and compliments her on her beauty, for what will be Cassandra's last time that she receives a compliment. The original Cassandra is touched and then Chip dies in her arms as Cassandra calls for assistance. The Doctor and Rose look on for a moment, then leave in the TARDIS.