Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens, often with the ultimate aim of developing new interventions against infectious diseases. Despite ethical concerns about research involving vulnerable populations, there are both scientific and ethical reasons to consider conducting more HCS in low- and middle-income countries where neglected diseases are often endemic. HCS researchers can reduce the risks to participants (and the risks of transmission from participants to others) by controlling multiple factors (eg those related to the laboratory environment, participant selection, the pathogen, and the timing of treatment); but HCS nonetheless raise important ethical issues, some of which may be particularly pertinent to HCS in endemic settings. This article provides background on HCS in general, as well as recent HCS in low- and middle-income countries, and an overview of the ethical issues associated with HCS in endemic settings.