Naïve T helper (T(H)0) cells can differentiate into one of two distinct populations: T(H)1 and T(H)2. Each population is characterized by the expression of specific cytokines and their ability to participate in cell-mediated or humoral immune responses. Recent efforts at identifying the molecular mechanisms through which T(H)0 cells become T(H)1 or T(H)2 cells have been promising. A number of transcription factors, including GATA-3 and T-bet, have been identified that promote the differentiation of T(H)0 cells and the maintenance of the differentiated cell phenotype. Dong and Flavell review recent findings on proteins that control the fate of T(H)0 differentiation, whether by promotion or inhibition, and discuss the role of epigenesis in the differentiation process.