The Doctor and Rose Tyler, in the TARDIS, chase a metal cylinder marked as "dangerous" through the time vortex. The cylinder skips out of the vortex, and the Doctor lands the TARDIS near the same space-time coordinates, in London during The Blitz air raids of World War II. The Doctor is intrigued by a young woman, Nancy, who warns him away from answering the phone that is part of the TARDIS disguise; doing so anyway, he hears a young boy asking for his "mummy" before the line drops. The Doctor follows Nancy to a well-to-do home, where she along with several other homeless children are partaking of a meal left by the homeowners before they left for shelter during a raid. A young boy in a gas mask knocks on the front door, and Nancy warns the Doctor not to let him in or even touch him, else he will become like the boy, "empty". As the rest of the children flee the house with the air raid over, the Doctor tracks down Nancy, a vagrant like the other children who knows that the boy is tied to what she believes was a bomb-like object that fell near Limehouse station, now under armed guard. Nancy also admits that her caring for the other children is a result of losing her brother Jamie in a recent air raid. After giving Nancy hope that the war is almost over, the Doctor leaves to investigate the hospital near the crash site, meeting Dr. Constantine. Constantine shows the Doctor a number of live patients, each unresponsive with a gas mask seemingly fused to their faces and marked with a scar on their hand, and then demonstrates that each respond identically and simultaneously to a loud noise. As Constantine starts to explain the first patient with this symptom was Nancy's brother, he transforms in front of the Doctor into another gas-mask wearing being.
During these events, Rose has seen the same boy on nearby rooftops, and tries to climb up a nearby rope to help him. Instead, she finds herself hanging precariously from a barrage balloon. She is rescued by Captain Jack Harkness, a freelance time agent himself with his own Chula spaceship, currently posing as a member of the RAF. Jack recognizes Rose as a time traveler herself, and after caring for rope burns on her hands using the ship's "nanogenes", starts to negotiate on the price of an item he has to sell. Rose bluffs, and asks Jack to take him to her partner, the Doctor. En route, Jack explains that the object is a Chula warship, which will be destroyed in another air raid in two hours.
Rose and Jack arrive in time to save the Doctor from the transformed Constantine and other patients. Escaping deeper into the hospital, Jack again attempts to sell the warship to the Doctor, but the Doctor calls the bluff. Jack admits it is only a Chula medical ship, and denies it has anything to do with the current outbreak. The episode ends as the three are trapped in a room as the transformed patients verge upon them, all asking for their "mummy", while Nancy, having returned to the house for more food, is similarly cornered by Jamie.
Continuing from the cliffhanger of "The Empty Child", the Doctor treats the beings like children, and faking a parent's anger, orders them to "go to their room" – thus causing them to return to their beds and, unbeknownst to him, saving Nancy from her brother Jamie. The Doctor, Rose and Jack go to Jamie's room where the Doctor realises that the being that was Jamie is still learning what it can do and soon will be too powerful to stop. The Doctor turns to discover Jamie, sent to his room by the Doctor's earlier orders, waiting in the doorway.
Escaping from Jamie and the other patients, they end up trapped in a room. Jack teleports back to his ship and uses Glenn Miller's "Moonlight Serenade" to prevent Jamie using the radio to track the Doctor and Rose. Challenged by Rose to dance while they wait, the Doctor accepts but is interrupted when they are transported to Jack's Chula ship. The Doctor uses the ship's nanogenes to heal a wound while Jack explains that he went renegade on the Time Agency when they stole two years of his memories.
Meanwhile, Nancy returns to the railyard to tell the other children they are not safe while they are with her. Telling them of her plan to head to the bomb site, Nancy does so but is captured by soldiers. Despite her pleas, she is left with a guard who has been infected and grows a gas mask on his face.
The Doctor, Rose, and Jack arrive at the bomb site and realise that the contagion is now airborne as the soldiers there begin to transform. Freeing Nancy, who saved herself by singing a lullaby to the transformed soldier, the Doctor investigates the 'bomb' which is actually the empty shell of a Chula medical transport. Realising that the ship also contained nanogenes, the Doctor deduces that the transformations are caused by nanogenes who have used Jamie's dead body in a gas mask as a template for all humans. Because the Chula were a warrior race and the transport was a battlefield ambulance, intended to return warriors to combat swiftly, the nanogenes have given the transformed beings enhanced abilities.
As they attempt to open the transport, it transmits a "call to arms" instructing all the alteredhumans to come to battle. The altered people from the hospital arrive at the railway station but stay at a distance, and the Doctor realises that since Jamie was the template, it is his mind that drives them, hence their collective obsession with finding a mother. A distraught Nancy claims that the situation is all her fault, and the Doctor realises that she is actually Jamie's teenage single mother, rather than his sister.
Jamie heads through the gate and approaches Nancy, still asking if she is his mummy. The Doctor instructs Nancy to tell Jamie the truth, and she tearfully does so, embracing her son. The nanogene cloud gathers around the two, and are able to identify Nancy's DNA as being that of a parent, and they reverse the transformation on Jamie, restoring him to life. The Doctor then scatters the nanogenes over the assembled zombies as he finally pulls off Jamie's gas mask, and they are all restored to perfect health.
As the German bomb falls onto the site, Jack uses his ship to capture it and remove it to the far reaches of space. Then the Doctor sets the medical transport to explode, thus destroying the technology and matching the historical records of an explosion at the site.
Aboard his ship, Jack finds he can neither stop the bomb from exploding nor abandon his ship, but is rescued when the TARDIS materialises at the rear of his ship. Joining the TARDIS crew, Jack watches as the Doctor and Rose dance in celebration.