Experimental inoculation of healthy volunteers with infectious agents has been practiced by investigators for many years to elucidate mechanisms of microbial virulence, disease pathogenesis, host immunity, and vaccine efficacy. Establishing these models requires detailed attention to scientific, ethical, and medical principles to ensure the safety of the participants and their community contacts and to generate valid observations that can be generalized to natural infections. This discussion provides examples of the potential values and applications of human challenge studies, addresses issues that must be considered in establishing a new challenge model, and examines the limitations of human data generated in this experimental setting.