Human infection challenge studies, which deliberately expose healthy volunteers to disease-causing infectious agents under carefully controlled conditions, offer a valuable method of biomedical research aimed at efficient initial efficacy testing of vaccine candidates, among other possible uses. They can be controversial, however, often evoking the response, “How can researchers do that?” Although Nazi physicians conducted egregious human challenge experiments on concentration camp inmates, many valuable challenge studies have been ethically and safely conducted over the past 40 years in which healthy volunteers have been exposed to infectious conditions such as influenza, cholera, and malaria. While these studies can produce temporary symptomatic distress, they have not to date been associated with lasting serious harms.