The Forkhead box protein P3 (FOXP3) is a master cell lineage modulator in CD4(+)CD25(+) natural regulatory T cell (Treg) development. The Treg set of cells, also called T suppressor cells, play an essential role in natural Treg-mediated suppression of various types of immune cells. Suppression can be manifest by a cell-cell contact set of events, and recent evidence also supports soluble mediators. FOXP3 was previous identified as a passive transcriptional repressor which associates with nuclear factor of activated T-cells, cytoplasmic, and calcineurin-dependent 2 (NFATc2) as well as several other transcriptional factors including nuclear factor kappa-B (NFkappaB) and acute myeloid leukemia 1(AML1)/runt-related transcription factor 1(RUNX1). We found FOXP3 could actively repress transcription by recruiting distinct histone acetyltransferases and histone deacetylases to function as a co-repressor complex. The identification of enzymatic factors operative as essential participants in FOXP3-mediated transcriptional repression provides a practical basis for therapeutically modulating the activity of FOXP3 in immune suppression. Here we briefly summarize recent progress in our understanding of the biochemistry of FOXP3-mediated transcriptional regulation.