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Having farewelled her mother (Camille Coduri) and Mickey (Noel Clarke), Rose Tyler (Billie Piper) joins the Doctor (David Tennant) in the TARDIS where he tells her that he has received a mysterious summons on his psychic paper to go to "Ward 26" which is in the hospital in New New York on the planet New Earth in the galaxy M87 in the year 5000000023.

Soon they are deep in the bowels of a futuristic hospital where a fellow time traveller, the Face of Boe (Struan Rodger) warns the Doctor of the deeds of the kittenish Sisters of Plenitude who run the hospital under the supercilious Matron Vasp (Dona Croll). The nurses appear to have conquered all diseases known to man but the facility holds a dark secret.

Also spying on Rose and the Doctor is an old enemy, Cassandra (Zoe Wanamaker), who was once human but now exists only as a face in a frame attended by her devoted servant Chip (Sean Gallagher). Keen to find a new host for her existence, Cassandra takes over Rose's body and then inhabits the Doctor's body as well. Will the time travellers discover the hospital's dark secret in time to save New Earth?