The forkhead family transcription factor Foxp3 is critical for the development and function of CD4(+)CD25(+) regulatory T cells (Tregs). A series of reports have begun to shed light on the precise role of Foxp3 in the regulation of the Treg transcriptome. Foxp3 can bind to specific gene elements, thereby altering transcription of target genes directly, and Foxp3 can alter the expression of genes encoding other transcription factors, thereby having an indirect effect on the transcription of target genes. Cells retaining aspects of Treg differentiation persist in the absence of Foxp3, which is suggestive of a Foxp3-independent aspect of Treg biology.