Self/non-self discrimination is a complex process that involves maintaining tolerance to autoantigens while preserving the potential to generate an effective humoral and cellular immune responses against invading pathogens. In the last decade, there has been a remarkable resurgence in research on suppressor or regulatory T cells. Few areas have captivated the attention of immunologists so vividly and entertained so many passionate debates. Indeed, CD4(+)CD25(+) Treg, which are at the very center of this fascination, have emerged as a dominant T cell population capable of mediating peripheral tolerance to autoantigens, but whose functions have now been extended to regulation of T cell responses directed to foreign antigens. However, a number of fundamental questions concerning the origin, phenotypic nature and mechanism of action of CD4(+)CD25(+) Treg cells remain elusive and misunderstood. We propose the existence of two general subsets of CD4(+)CD25(+) Treg cells, naturally-occurring and induced, that differ in their origin, developmental and activation requirements, and mechanism of action.