Dengue is a arboviral infection that represents a major global health burden. There is an unmet need for effective dengue therapeutics to reduce symptoms, duration of illness and incidence of severe complications. Here, we consider the merits of a dengue human infection model (DHIM) for drug development. A DHIM could allow experimentally controlled studies of candidate therapeutics in preselected susceptible volunteers, potentially using smaller sample sizes than trials that recruited patients with dengue in an endemic country. In addition, the DHIM would assist the conduct of intensive pharmacokinetic and basic research investigations and aid in determining optimal drug dosage. Furthermore, a DHIM could help establish proof of concept that chemoprophylaxis against dengue is feasible. The key challenge in developing the DHIM for drug development is to ensure the model reliably replicates the typical clinical and laboratory features of naturally acquired, symptomatic dengue.