Regulatory T (T(Reg)) cells constitute a unique T-cell lineage that has a crucial role in immunological tolerance. Several years ago, forkhead box P3 (FOXP3) was identified as the transcription factor that was responsible for determining the development and function of these cells. However, the underlying mechanisms that are involved in the regulation of the FOXP3 gene remain unclear and therefore preclude accurate identification and manipulation of T(Reg) cells. In this Progress article, we summarize recent advances in understanding how FOXP3 expression is controlled and highlight evidence suggesting that epigenetic regulation of the FOXP3 locus contributes to its role as a lineage-specification factor.