This chapter introduces the region, peoples, and historical changes underway in the mid-nineteenth century where the book begins. The lands lie along the Mackenzie and Yukon rivers and their tributaries, where waters flow north along the Mackenzie River into the Beaufort Sea and south-west down the Yukon River across into Alaska. These are the homelands of Inuvialuit, Gwich’in, Tłı̨chǫ, Dene, Tr’ondëk Hwëch’in, Tagish, Tutchone, Dënesųłıné, and Métis. This chapter introduces these peoples as well as the earliest Euro-Canadian colonizers and settlers: fur traders, explorers, missionaries, police, state officials, and their families who arrived in the nineteenth century and describes the book’s objectives: to learn about the historical significance of major northern epidemics before 1940 from those who survived; to use ecological approaches to disease to understand how colonialism shaped northern health; and to demonstrate the influence of flaws ideas about isolation and vulnerability in shaping past interpretations of the role of disease in the process of colonization.