Discredited a few years ago, active suppression is now commonly considered as a key mechanism avoiding auto-reactivity and development of potentially harmful immune responses, and in some circumstances, as an obstacle to successful vaccination. A large quantity of literature identifies naturally occurring CD4+CD25+ T cells as key suppressor cells involved in the control of many pathophysiological diseases. Manipulation of these cells and control of their function offers new perspectives for the treatment of auto-immune and inflammatory diseases and enhancement of vaccine efficacy. Such clinical interventions require a better understanding of the conditions of expansion/activation of CD4+CD25+ T cells and deciphering of their mechanism of suppression, which remains incomplete and sometimes controversial.