Scarlet fever in the 1860s affected people along the Yukon and Mackenzie rivers and was perceived at the time as the most significant nineteenth-century epidemic. It was also connected to a much larger scarlet fever pandemic. Combined with influenza, scarlet fever moved down rivers, through trade posts, and into camps, illuminating how local relations with people and the land shaped the pandemic. This chapter conveys the scale of this sickness through estimates of deaths and the geographic extent of disease spread. The chapter then assesses the effects of ill health and mortality, the loss of adults and children, on the larger processes of colonial change underway in the nineteenth century, including the creation of northern residential schools.