Immunological tolerance is one of the fundamental concepts of the immune system. During the past decade, CD4+CD25+-regulatory T cells have emerged as key players in the development of tolerance to autoantigens as well as to foreign antigens. Still many questions remain illusive regarding the basic properties of CD4+CD25+-regulatory T cells. This review aims to recapitulate some of the current understandings about the phenotype, function and clinical relevance of murine and human CD4+CD25+-regulatory T cells.