Schistosoma mansoni infection invariably results in liver fibrosis of the host. This fibrosis may be represented by small focal areas of chronic inflammation and excess extracellular matrix deposited in periovular granulomas, distributed in variable numbers at the periphery of the portal vein system. This is the outcome of 90% of the infected population in endemic areas. Conversely, a minority of infected individuals develop extensive disease with numerous granulomas along the entire extension of the portal spaces. This latter situation is mainly dependent on special hemodynamic changes created by a heavy worm load, with the subsequent production of numerous eggs and represents a severe form of a peculiar chronic hepatopathy. Thus, host–parasite interactions in schistosomiasis help us to understand a number of important features of liver fibrosis: its initiation and regulation, the significance of accompanying vascular changes, the dynamics of fibrosis formation and regression with antiparasitic treatment; host genetic and immunological contributions, and the pathophysiology of portal hypertension.