Based on the life of renowned New York physician Dr. David Hosack, the story takes place in 1820s Manhattan during an impending yellow fever epidemic.
Jumping forward 20 years into the future, Dr. Hosack and apprentice Albert Dash realize a yellow fever outbreak is upon them after treating a man who is killed by the disease.
Hosack sends his apprentice to discover all he can about where their patient may have contracted the disease, and eventually comes upon the conclusion that it was brought in the hull of a ship, the Belladonia, from Kingston, Jamaica.
Sensing victory in their grasp, the group behind the aqueduct plan begins pitching their idea, which seems very promising because of the lack of clean, drinkable water in the city.
When yellow fever breaks out in Philadelphia, a panic rises up among Manhattan citizens, but it is slowly pushed to the back of their minds through reassurances by Laidlaw, the Mayor, and Casey, along with the arrival of prominent English stage actor Edmund Leadbetter, who is set to perform at the rival theater from Vera Laidlaw, set to make her stage debut as Ophelia in Hamlet.
Laidlaw and Casey flee to Ambleside and the home of Samuel Geyer while Manhattan becomes a scene of panic, as yellow fever infection becomes widespread.
Albert is offered a professorship at Columbia in botany, but declines when Dr. Hosack issues the invitation, saying he and Virginia plan to travel west, where he may open his own hospital and she may run it.