Sulfadoxine-pyrimethamine (SP) is the standard of care for Plasmodium falciparum malaria chemoprevention among pregnant women, infants and children. Developing alternative chemoprevention products and other prevention products, such as vaccines and monoclonal antibodies, requires significant investment. However, knowledge gaps surrounding the activity of SP and resistance put these investments at risk. Therefore, we reviewed SP’s combined antimalarial action, including the individual antiplasmodial components, other antimicrobial effects, impact on malaria immunity development and continued effectiveness in settings with high SP resistance. We created a roadmap of non-clinical and clinical evidence to better understand the effectiveness of SP for chemoprevention and inform the development of new prevention tools.