The mechanisms underlying the failure to control the growth and systemic spread of Leishmania parasites in human visceral leishmaniasis (VL) are not well understood. Although the absence of antigen-specific Th1 responses in the peripheral blood mononuclear cells from VL patients is thought to be causally related to disease progression, the finding that these patients also express elevated interferon-gamma mRNA in lesional tissue, as well as elevated serum levels of proinflammatory cytokines, suggests that their immunological defect cannot be explained simply by immune tolerance or Th2 polarization. As a possible homeostatic mechanism to control persistent infection-induced inflammation, elevated levels of the regulatory cytokine interleukin (IL)-10 have been reported repeatedly in clinical studies of VL. Here, we review the studies with relevance to immune responses in human VL and highlight the central role that IL-10 might have in the pathogenesis of VL and as a target for immune-based therapy.