CD4+CD25+ regulatory T (Treg) cells have emerged as important regulators of immune responses but the mechanisms through which Treg cells mediate suppression are still unclear. Recently, several studies have identified murine models of spontaneous autoimmunity or genetically engineered mice in which the Treg cells function normally but the CD4+CD25- T effector (Teff) cells are resistant to Treg-mediated suppression. Here, we postulate that the activation status of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in Teff cells is a primary determinant of Teff cell sensitivity to Treg cell-mediated suppression, and that when the PI3K-Akt pathway is hyperactivated in Teff cells, these cells are resistant to Treg cell-mediated suppression. We further postulate that this paradigm can mechanistically link abnormalities in the PI3K-Akt pathway to the development of autoimmunity.