Regulatory T (Treg) cells are a developmentally and functionally distinct T cell subpopulation that is engaged in sustaining immunological self-tolerance and homeostasis. The transcription factor Foxp3 plays a key role in Treg cell development and function. However, expression of Foxp3 alone is not sufficient for conferring and maintaining Treg cell function and phenotype. Complementing the insufficiency, Treg-cell-specific epigenetic changes are also critical in the process of Treg cell specification, in regulating its potential plasticity, and hence in establishing a stable lineage. Understanding how epigenetic alterations and Foxp3 expression coordinately control Treg-cell-specific gene regulation will enable better control of immune responses by targeting the generation and maintenance of Treg cells.