Schistosomiasis remains a major worldwide public health problem in several endemic areas despite implementation of control measures. Vaccination would be an effective, long-term treatment option for future control of schistosomiasis. Although several parasite antigens have been identified as schistosomiasis vaccine candidates, major hurdles must still be overcome to develop a vaccine suitable for clinical trials in the field. Better understanding of immune responses to Schistosoma infection in both animal models and humans suggests that development of a vaccine is possible. The purpose of this review is to summarize the mechanisms of protective immunity against Schistosoma infection and to provide perspective on the development of a vaccine.