As the Tenth Doctor powers up the TARDIS, Rose says good-bye to Jackie and Mickey at the Powell Estate. Although Jackie and Mickey sadly watch the TARDIS fade away, inside the ship Rose is all smiles as she asks where they are going next. The Doctor tells her that they are going further than they have ever gone before.

The TARDIS materialises on New Earth, in the year five billion and twenty-three. Following the destruction of Earth, humanity became nostalgic and settled a new planet with similar gravity and atmosphere in the galaxy M87. Rose is delighted at the beauty of the new world, the sight of the futuristic city of New New York in front of them and the smell of apple-grass, reminiscing about their "first date" in the year five billion. However, the two travellers are being observed by a robot spider controlled by Chip, a small, pale man with multiple tattoos. Chip takes his orders from Lady Cassandra, who is still alive and recognises Rose.

The Doctor and Rose head for a large hospital building, the Doctor having been summoned by a telepathic message displayed on his psychic paper: "Ward 26, Please Come". The hospital is run by humanoid feline nuns belonging to an order called the Sisters of Plenitude. Trying to find the right ward, the Doctor and Rose enter separate lifts, which give each of them a disinfecting shower. However, Chip has overridden Rose's lift controls, and diverts her to the basement. He beckons her forward, calling her by name, which rouses her suspicions.

In the ward, the Doctor is escorted around by Sister Jatt. He observes that the patients all have diseases which are supposed to be incurable, but yet the Sisters are able to cure them. However, the nuns are evasive about what precisely is in the coloured solutions that are given to the patients. The Doctor then recognises who it must be that has called him here — the Face of Boe. He is being tended to by Novice Hame, who tells the Doctor that the Face is dying of old age.

Meanwhile, Rose explores the basement warily, and finds an old projector showing a film of a party, with several men surrounding a blonde woman with a very familiar voice. That same voice makes Rose turn to see Cassandra, looking just as she did when Rose last saw her: a piece of skin stretched out on a frame above a brain jar. Cassandra had been reconstructed from another piece of her skin, and Chip (a forced-growth clone devoted to Cassandra) smuggled her into the hospital, where he has been tending to her ever since. However, Cassandra has discovered that the Sisters are hiding something, and to find out what, she needs Rose's help… or rather her body. Using a device called a psychograft, Cassandra implants her consciousness over Rose's own, allowing her own brain to die.

In the ward Novice Hame tells the Doctor that legend has it that the Face has lived for thousands, perhaps millions of years and that he will give his dying message to a wanderer without a home. The Doctor realises that he fits the description in the legend, but says nothing. Below, Cassandra reads Rose's surface thoughts and discovers that the man with Rose is the Doctor, with a new face. She goes to meet him.

"Rose's" odd behaviour raises the Doctor's suspicions, especially when she kisses him passionately and later shows anachronistic knowledge of the hospital's computer systems. With her help, however, they enter Intensive Care and discover the horrifying secret behind the hospital: hundreds of individual pods containing artificially grown human beings infected with a thousand different diseases, a human farm to breed cures. If the subjects become healthy enough to speak or move, the Sisters kill them. The Doctor, in a rage, confronts Novice Hame about this, but she argues that these artificial humans are just "flesh". It was necessary to cope with the influx of patients and diseases. The Doctor also demands the Sisters reverse what they have done to Rose, not realising that Cassandra has taken her over. "Rose" admits she is Cassandra, and knocks out the Doctor with some drugged perfume.

While the Doctor is trapped in a pod about to be injected with diseases, "Rose" tries to blackmail Matron Casp, demanding payment to keep quiet about the Sisters' actions. When Casp declines and threatens her physically, "Rose" releases the Doctor and some of the plague carriers as a distraction. They, in turn, release the rest, and the zombie-like mass of them begin to lurch through the hospital, infecting and killing anyone that touches them almost instantly, with Sister Jatt the first to die.

After failing to find a way out through the basement, the Doctor demands Cassandra release Rose, threatening her with the sonic screwdriver. Cassandra transfers her consciousness to the Doctor instead. The "Doctor" and Rose climb up the lift shaft, pursued by the carriers. Matron Casp tries to stop them, but is infected and falls down the shaft, screaming. Cassandra transfers herself to a plague carrier so that the Doctor can use the sonic screwdriver to unseal the lift doors, and then jumps back into Rose. "Rose" is momentarily shocked and moved by the loneliness the carriers feel, not being able to touch or be touched all their lives.

The Doctor and "Rose" reach Ward 26, which seems to be the only place still untouched by the carriers. The Doctor takes all of the intravenous solutions and straps them to his body. Together with "Rose", he slides back down the shaft to the lift car, where he empties the solutions into the disinfectant reservoir. The Doctor opens the doors, luring several plague carriers inward as "Rose" starts the shower. The spray drenches the carriers, curing them. The Doctor encourages them to pass it on, and they wander back out to spread the cure to the others.

The surviving Sisters are arrested by the New New York Police Department, and the cured New Humans (as the Doctor calls them), are to be taken into care. At that moment, the Doctor remembers the Face. No longer dying, the Face tells the Doctor telepathically that he had grown tired of the universe, but the Doctor had taught him to look at it anew. The Doctor asks the Face about his message, but he enigmatically replies that it can wait for their third and final meeting. The Face then teleports away.

The Doctor now orders Cassandra out of Rose's body. Cassandra transfers her consciousness to a willing Chip instead, but his cloned body begins to fail, and Cassandra accepts her impending, true death; the New Earth has no place for people like her and Chip. The Doctor does one last thing for Cassandra, taking her back to the party seen earlier, to see herself on the last night someone had called her beautiful. "Chip" approaches the Cassandra of the past and tells her just that, and collapses into the younger Cassandra's arms as she comforts "him". As the older Cassandra finally dies, the Doctor and Rose silently leave in the TARDIS.