Critical knowledge gaps regarding infection withMycobacterium ulcerans, the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and vaccines for prevention of this neglected tropical disease. Here, we review the current understanding of host–pathogen interactions and correlates of immune protection to explore the case for establishing a controlled human infection model ofM.ulceransinfection. We also summarise the overarching safety considerations and present a rationale for selecting a suitable challenge strain.