Immunity against schistosomes includes anti-infection immunity, which is mainly active against invading larvae in the skin, and anti-disease immunity, which controls abnormal fibrosis in tissues invaded by schistosome eggs. Anti-infection immunity is T-helper 2 (Th2) cell-dependent and is controlled by a major genetic locus that is located near the Th2 cytokine locus on chromosome 5q31-q33. Mutations in the gene encoding interleukin (IL)-13 that decrease or increase IL-13 production account, at least in part, for that genetic control. In contrast, protection against hepatic fibrosis is dependent on interferon (IFN)-gamma and is controlled by a major genetic locus that is located on 6q23, near the gene encoding the IFN-gamma receptor beta chain. Mutations that modulate IFN-gamma gene transcription are associated with different susceptibility to disease. These data indicate that IL-13 in the skin and IFN-gamma in the liver are key players in protective immunity against schistosomes. These roles relate to the high anti-fibrogenic activities of IFN-gamma and to the unique ability of IL-13 in Th2 priming in the skin and in the mobilization of eosinophils in tissues. The coexistence of strong IFN-gamma and IL-13-mediated immune responses in the same subject may involve the compartmentalization of the anti-schistosome immune response between the skin and the liver.