Urogenital schistosomiasis, caused by the Schistosoma haematobium parasite, is a global cause of morbidity and mortality and affects millions of people each year. The mass drug administration (MDA) of praziquantel (PZQ) is a vital intervention to treat schistosome infections and eliminate schistosomiasis as a public health problem. After decades of use, variable PZQ efficacy and persistent schistosome infections have been reported across multiple schistosome-endemic African countries. However, there is a paucity of information on the factors that influence the efficacy of a PZQ treatment and contribute to the persistence of infection, particularly in schistosome-exposed populations where the drug is commonly used. To address this, I examined the factors that influence individual responses to PZQ and how these contribute to variable PZQ efficacy. This focused on alterations to PZQ metabolism, which regulates the concentration of the schistosome-killing PZQ, and thus can be a crucial determinant of PZQ efficacy and adverse drug reactions (ADRs). During a review of published studies, I identified several drug and host-related factors, such as drug-drug interactions (DDIs) and the liver’s capacity to metabolise PZQ, that influenced the systemic concentrations of PZQ via altered PZQ metabolism, and discussed the resultant impact on PZQ efficacy. This review also highlighted gaps in the research regarding pharmacogenetic (PGx) and metabolomic studies. Consequently, I characterised PGx variations in PZQ- metabolising cytochrome P450 (CYP) enzymes and determined associations between each detected variant and the efficacy of PZQ treatment in S. haematobium-infected Zimbabweans. Four single nucleotide polymorphisms (SNPs) across the CYP1A2, CYP2D6 and CYP3A5 enzymes were significantly associated with PZQ treatment outcome, including genotypes that increased the odds of an individual clearing or not clearing schistosome infection. A further study using in vivo analyte concentrations detected no associations with PZQ efficacy. Yet, there were significant associations between variants in the CYP1A2 and CYP2C9 enzymes and in vivo analyte concentrations indicative of increased metabolism and decreased PZQ exposure. Both PGx studies provided insight into the drug-gene interactions in schistosome-infected patients during a PZQ treatment and suggested that the PGx impact on PZQ exposure and efficacy may be underestimated in the diverse African populations where PZQ is utilised. To determine if variable PZQ efficacy and persistent schistosome infections occurred during MDAs in Zimbabwe, I identified persistent hotspots of S. haematobium infection prevalence (PPHS) and hotspots of decreasing efficacy of PZQ (EPHS). Further, the risk factors of hotspot emergence were evaluated, and EPHS were not identified as a primary cause for PPHS based on these analyses. Initial infection intensity was significantly higher in PPHS than in responder districts, providing valuable information on the possibility of early identification of persistent schistosome infections to improve on current control strategies. However, there was no clear predictor of EPHS occurrence. Overall, this thesis highlighted key factors that influence an individual’s response to a PZQ treatment, including multiple PGx determinants which were previously underreported. Together, this thesis produced significant novel data towards the characterisation of the host factors that contribute towards variable PZQ efficacy, and in the identification of hotspots of persistent infections. Together, these findings will inform policymakers on the factors that influence PZQ efficacy to improve schistosomiasis control and eliminate this disease.