The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) conducted large field studies on schistosomiasis control and elimination in Africa. All of these studies, carried out in low-, moderate-, and high-prevalence areas, resulted in a reduction in prevalence and intensity of Schistosoma infection after repeated mass drug administration (MDA). However, in all studies, there were locations that experienced minimal or no decline or even increased in prevalence and/or intensity. These areas are termed persistent hotspots (PHS). In SCORE studies in medium- to high-prevalence areas, at least 30% of study villages were PHS. There was no consistent relationship between PHS and the type or frequency of intervention, adequacy of reported MDA coverage, and prevalence or intensity of infection at baseline. In a series of small studies, factors that differed between PHS and villages that responded to repeated MDA as expected included sources of water for personal use, sanitation, and hygiene. SCORE studies comparing PHS with villages that responded to MDA suggest the potential for PHS to be identified after a few years of MDA. However, additional studies in different social-ecological settings are needed to develop generalizable approaches that program managers can use to identify and address PHS. This is essential if goals for schistosomiasis control and elimination are to be achieved.