In the first episode, the epidemic is traced back to its source in the parish of St Giles in the Fields, now at the heart of London's theatre district. The programme also examines the symptoms of the disease and uncovers new research into the plague bacteria that could overthrow accepted ideas about how the infection was spread.

Xand van Tulleken visits Samuel Pepys' parish church and discovers the sad tale of the Poole family, who within 11 days lost all five of their children. He also heads to Eyam in Derbyshire, revealing the heroic story of self-sacrifice that saw all 700 villagers lock themselves in to try to stop the disease spreading to surrounding areas. Raksha Dave trials 17th-century disinfection methods and reveals a surprising substitute that can be just effective as modern antibacterial cleaners.

In the second episode, Xand heads to St Barts hospital to look back at historical records which show that nursing staff stayed behind and risked their lives to help the sick. Elsewhere, John investigates why infection rates were so different between the rich and poor, examining clothes typical for each group in the 17th century.