The interleukin (IL)-4 driven, polarized T-helper 2 cell (Th2) response that controls non-healing infection with Leishmania major in BALB/c mice has long been embraced as the underlying principle with which to consider the pathogenesis of non-healing and systemic forms of leishmaniasis in humans. The inability, however, to reveal a Th2 polarity associated with non-curing clinical disease has suggested that alternative cells and cytokines are involved in susceptibility. In this review, various mouse models of non-curing infection with L. major and other Leishmania species are re-examined in the context of the suppression mediated by IL-10 and regulatory T (Treg) cells. These activities are revealed in L. major-infected BALB/c IL-4 knockout (KO) and IL-4Ralpha KO mice and especially in non-cure resistant mice that do not default to a Th2 pathway as a result of inherent defects in Th1 differentiation. In contrast to the extreme BALB/c susceptibility arising from an aberrant Th2 response, non-cure in resistant mice arises from an imbalance in Treg cells that are activated in the context of an ongoing Th1 response and whose primary function may be to suppress the immunopathology associated with persistent antiparasite responses in infected tissues.