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 re-emergence of the idea that regulatory T (T_Reg) cells are a central mechanism of immune regulation. These insights have raised fundamental questions concerning what constitutes a T_Reg cell, where they develop and what signals maintain T_Reg-cell populations in a functional state. Here, we propose the existence of two subsets of CD4⁺ T_Reg cells — natural and adaptive — that differ in terms of their development, specificity, mechanism of action and dependence on T-cell receptor and co-stimulatory signalling.