Rose (Billie Piper) bids farewell to her mother (Camille Coduri) and Mickey (Noel Clarke) for a new trip in the TARDIS with the newly regenerated Doctor (David Tennant)...

The TARDIS arrives five billion years in the future, after the death of the Earth (in "The End of the World"). Humanity's remnants have scattered across the stars and settled on a new planet called "New Earth," complete with a sprawling city called New New York, a huge medical hospital... and Lady Cassandra (Zoe Wanamaker), who survived her last encounter with the Doctor and has now discovered their arrival. As the Doctor and Rose enter the hospital facility -- after a cryptic message is received on the Doctor's psychic paper -- the two are separated, where Rose is brought down into the subfloors and discovers that Cassandra is very much alive, her brain having lived beyond the death of her skin-sheet. Rose is helpless as Cassandra's bioengineered protege Chip (Sean Gallagher) sets up a device which proves to release Cassandra's energy from the brain-tank... right into Rose's body.

Meanwhile, the Doctor visits the upper floors, where he meets Novice Hame (Anna Hope), one of the Sisters of Plenitude, the caretakers of the hospital -- and discovers the presence of the Face of Boe, who called him here. Their brief visit is shortlived, when he discovers that one of the patients, the Duke of Manhattan (Michael Fitzgerald) has been cured of a mysterious ailment, one that he thought was uncurable for this time zone, by Matron Casp (Dona Croll), the manager of the hospital. Suddenly, Rose -- or rather, Cassandra in Rose's body -- returns to the Doctor, where he begins to suspect something strange is going on.

The Doctor and "Rose" enter a huge cavernous area of the hospital where they discover the Sisters have been breeding humanoid stock in order to inflict them with every disease known to science... ostensibly to find cures for them, but at the price of the life of the victims. The Doctor confronts the Sisters, but Cassandra reveals herself, trapping the Doctor in one of the disease vats. She then releases all of the other patients, who start a rampage, killing Matron Casp and running amok through the hospital. The Doctor, Cassandra-Rose and Chip escape to the subbasement, Cassandra swapping bodies with the Doctor and Rose all the while. It takes a visit inside one of the disease rats, however, to make her realize the suffering she's witnessed.

Using the decontamination showers inside the public elevators, the Doctor curse the disease rats, releasing them from their bondage. The miracle cures of the hospital also cure the Face of Boe, who tells the Doctor that he will tell him his secret one day... but he will only reveal his secret when he has died, and now he can live a bit longer.

Cassandra gives up Rose's body, fleeing into the willing Chip, who takes this one final act on his mistress' behalf. The Doctor and Rose take Cassandra-Chip to a party many years before, on the very last night Cassandra said someone told her she was beautiful. As the TARDIS departs, Cassandra-Chip falls over and dies in the arms of her earlier self.