Controlled human infection models have been in use for decades, supporting vaccine development. For schistosomiasis, no licensed vaccine is available, despite urgent need. A controlled human infection model for schistosomiasis has been developed at the Leiden University Medical Center. This model uses a single-sex schistosome infection in order to prevent egg production and has now been tested with both male-only and female-only infections. Although symptoms of the acute schistosomiasis syndrome occur in a dose-dependent fashion, the model is generally well-tolerated. Circulating anodic antigen has been successfully used to detect the infection, resulting in an attack rate of nine out of eleven participants who received 20 male cercariae and six out of ten participants receiving 20 female cercariae. Participants were treated with praziquantel; however, treatment was not successful in four out of ten participants in the female infection group, although most self-cleared during follow-up. The male-only model is now sufficiently developed to serve as a challenge model for testing the efficacy of novel vaccines and drugs.