Summary:  Schistosomiasis is a serious global helminthic disease, in which the main immunopathology consists of a granulomatous and fibrosing reaction against tissue-trapped parasite eggs. The severity of this inflammatory process, the product of a CD4+ T-cell-mediated immune response against parasite egg antigens, is, however, markedly uneven, both in human patients and among mouse strains in an experimental model. Severe schistosomiasis is associated with persistently elevated pro-inflammatory T-helper-1 (Th1)-type cytokines, whereas milder pathology is present when Th2 cytokines dominate. This scenario is supported by the pronounced pathology resulting from the obliteration of pathways that facilitate Th2 differentiation and by the development of more intense lesions in mouse strains that fail to downregulate the Th1 response. Genetically prone high-pathology mice have a higher proportion of CD4+ T cells in lymph nodes and granulomas, in which the Th1 phenotype is driven by interleukin-12; they also develop a dominant repertoire against peptide 234–246 of the major Sm-p40 egg antigen, utilizing a strikingly restricted T-cell receptor structure that involves Vα11.3β8. In turn, low-pathology mice exhibit enhanced CD4+ T-cell apoptosis, which contributes to limit pathology. The definition of distinctive immune profiles associated with polar forms of schistosomiasis opens opportunities for targeted immuno-intervention in individuals suffering from or at risk of severe disease.