In the periphery, tolerance to self antigens is mainly mediated by the CD4⁺CD25⁺FOXP3⁺ subset of regulatory T cells, which can suppress the activity of autoreactive T cells that have escaped deletion in the thymus. The essential role of the transcription factor FOXP3 (forkhead box P3) in the development and function of these regulatory T cells has been well documented. It is also clear that regulatory T cells and effector T cells respond differently to T-cell receptor stimulation. In this Opinion article, we propose that these differences in responses are mediated by FOXP3, and are manifested by alterations in biochemical signalling pathways, patterns of gene expression and the appearance of cell-surface homing receptors.