Regulatory T cells (Tregs) promote immune tolerance and protect against autoimmunity. Tregs develop in the thymus, and their differentiation and acquisition of suppressive function require expression of the transcription factor Foxp3. Although several transcription factors have been identified that turn on Foxp3 gene expression, how Foxp3 remains turned off in non-Tregs is not well understood. Liu et al. have demonstrated that a regulator of cytokine signaling, PIAS1, represses Foxp3 expression by chromatin modification. PIAS1 promoted the methylation of the Foxp3 promoter by recruiting methyltransferases to inhibit expression. PIAS-deficient mice have more Treg cells than controls, and they appear to be protected against the development of experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis.