Approximately 200 000 000 people have schistosomiasis (schistosome infection). Among the schistosomes, Schistosoma haematobium is responsible for the most infections, which are present in 110 million people globally, mostly in sub-Saharan Africa. This pathogen causes an astonishing breadth of sequelae: hematuria, anemia, dysuria, stunting, uremia, bladder cancer, urosepsis, and human immunodeficiency virus coinfection. Refined estimates of the impact of schistosomiasis on quality of life suggest that it rivals malaria. Despite S. haematobium's importance, relevant research has lagged. Here, we review advances that will deepen knowledge of S. haematobium. Three sets of breakthroughs will accelerate discoveries in the pathogenesis of urogenital schistosomiasis (UGS): (1) comparative genomics, (2) the development of functional genomic tools, and (3) the use of animal models to explore S. haematobium-host interactions. Comparative genomics for S. haematobium is feasible, given the sequencing of multiple schistosome genomes. Features of the S. haematobium genome that are conserved among platyhelminth species and others that are unique to S. haematobium may provide novel diagnostic and drug targets for UGS. Although there are technical hurdles, the integrated use of these approaches can elucidate host-pathogen interactions during this infection and can inform the development of techniques for investigating schistosomes in their human and snail hosts and the development of therapeutics and vaccines for the control of UGS.