Controlled human infection (CHI) trials, in which healthy volunteers are experimentally infected, can accelerate the development of novel drugs and vaccines for infectious diseases of global importance. The use of CHI models is expanding from around 60 studies in the 1970s to more than 120 publications in this decade, primarily for influenza, rhinovirus, and malaria. CHI trials have provided landmark data for several registered drugs and vaccines, and have generated unprecedented scientific insights. Because of their invasive nature, CHI studies demand critical ethical review according to established frameworks. CHI-associated serious adverse events are rarely reported. Novel CHI models need standardised safety data from comparable CHI models to facilitate evidence-based risk assessments, as well as funds to produce challenge inoculum according to regulatory requirements. Advances such as the principle of controlled colonisation, the expansion of models to endemic areas, and the use of genetically attenuated strains will further broaden the scope of CHI trials.