Forkhead box protein P3 (FOXP3) contributes to a unique transcriptional signature and serves as a functional marker of CD4(+)CD25(+) natural regulatory T cells. Dysfunction of FOXP3 in human is associated with fatal autoimmune disease known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) or X-linked autoimmunity-allergic disregulation syndrome (XLAAD). FOXP3 also can act as a breast tumor suppressor of the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog (avian)) (Her2/neu) gene. While the suppressive functions of FOXP3 in maintaining the immune balance between tolerance and autoimmunity are obvious, the underlying molecular mechanism remains almost entirely undefined. Recent studies indicate that FOXP3 may form a dynamic superamolecular complex with a variety of molecular partners including transcription factors and enzymatic proteins to regulate transcription. How the FOXP3 ensemble changes in response to T-cell receptor signals and/or proinflammatory signal remains unclear although work from this laboratory has revealed its complexity. Structural information on FOXP3 complex may offer novel functional insights, as well as facilitate the development of rational means to modulate regulatory T-cell function in various human diseases.