One of the greatest challenges faced by William Clark and Meriwether Lewis on their 1804–6 Corps of Discovery expedition was that of medical emergencies on the trail. Without an attending physician, even routine ailments and injuries could have tragic consequences for the expedition’s success and the safety of its members. Of these dangers, the most insidious and potentially devastating was the slow, painful, and oftentimes fatal ravage of venereal disease. Physician Thomas P. Lowry delves into the world of nineteenth-century medicine, uncovering the expedition’s very real fear of venereal disease. Lewis and Clark knew they were unlikely to prevent their men from forming sexual liaisons on the trail, so they prepared for the consequences of encounters with potentially infected people, as well as the consequences of preexisting disease, by stocking themselves with medicine and the latest scientific knowledge from the best minds in America. Lewis and Clark’s expedition encountered Native peoples who experienced venereal disease as a result of liaisons with French, British, Spanish, and Canadian travelers and had their own methods for curing its victims, or at least for easing the pain it inflicted. Lowry’s careful study of the explorers’ journals sheds new light on this neglected aspect of the expedition, showing in detail how sex and venereal disease affected the men and their mission, and describes how diverse peoples faced a common threat with the best knowledge and tools at their disposal.