The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the reemergence of the idea that regulatory T cells (Treg) are key players in immune regulation. These insights have raised fundamental questions concerning the definition of a Treg and what exactly constitutes T-cell–mediated suppression, identification of the signals and the cellular environment that promote the development and differentiation of these cells, and which signals maintain the homeostasis of the immune system. Thus far, the different models where Treg have been characterized cannot fully account for CD4+ CD25+ T cells. In this article, the authors propose the coexistence of two specialized types of CD4+ Treg—innate and acquired—that differ in terms of their development, specificity, mechanisms, and sites of action.