Tolerance to self antigens is established in two ways: first in the thymus through the deletion of thymocytes expressing self-reactive T cell receptors; and second, in the periphery through multiple mechanisms involving deletion, anergy, and suppression. Dominant tolerance to self antigens in the periphery is primarily the function of the CD4(+)CD25(+)FOXP3(+) subset of T cells, which have the capability of suppressing autoreactive T cells that have escaped deletion during thymic selection. The essential role of the transcription factor FOXP3 in the development and function of these cells has been well documented. However, the underlying mechanisms by which FOXP3 controls this process are less well understood. This review will focus on the role of FOXP3 in regulating CD4 T cell function in both humans and mice, with an emphasis on recent work in human systems.