In this chapter we explore the intricate relationship between schistosomes and their human hosts, delving into the biology, pathogenesis, clinical manifestations, and diagnostics of schistosomiasis. Prevalent for millennia, the disease remains a significant global health challenge, particularly in sub-Saharan Africa. The life cycle of schistosomes involves freshwater snails, with transmission to the definitive host, such as humans, linked to water exposure. Acute and chronic stages manifest with diverse symptoms, ranging from fever and hematuria to severe organ damage, including fibrosis and bladder cancer. Advanced diagnostics, such as molecular and serological methods, complement traditional microscopy but are less accessible in endemic regions. Clinical interventions focus primarily on praziquantel, with significant reversibility of symptoms even in late stages. The chapter underscores schistosomiasis as a “One Health” issue, requiring integrated approaches targeting humans, snails, and environmental water sources. It highlights the disease’s socioeconomic impact and its interplay with other infections, including HIV. Comprehensive elimination strategies encompassing diagnostics, treatment, and environmental control are emphasized to combat this ancient yet persistent parasitic challenge.