There is growing evidence that regulatory T cells and, in particular, the endogenous CD4+CD25+ T cells (T-reg) are playing a fundamental role in the infectious process due to the protozoan parasite Leishmania. Endogenous CD4+CD25+ T cells are a population of regulatory T cells, recently, described for their capacity to control excessive or misdirected immune response. During human or murine Leishmaniasis, many features characteristic of T-reg function, such as high levels of IL-10, transforming growth factor-beta (TGF-beta) or immunosuppression, have been extensively described. Recent reports formally involved T-reg in the control of Leishmania major infection. Such control occurs by modulation of the effector immune response; in susceptible mouse strains, CD4+CD25+ T cells suppress excessive T helper (Th)2 response, while in genetically resistant mouse strains, they control protective Th1 responses, allowing for parasite survival and maintenance of memory response. The mechanisms and consequences of such control in both susceptible or resistant mouse strains are discussed.