Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper type 2 cells. Here we show that IRF4 is also critical for the generation of interleukin 17–producing T helper cells (T_H-17 cells), which are associated with experimental autoimmune encephalomyelitis. IRF4-deficient (Irf4^−/−) mice did not develop experimental autoimmune encephalomyelitis, and T helper cells from such mice failed to differentiate into T_H-17 cells. Transfer of wild-type T helper cells into Irf4^−/− mice rendered the mice susceptible to experimental autoimmune encephalomyelitis. Irf4^−/− T helper cells had less expression of RORγt and more expression of Foxp3, transcription factors important for the differentiation of T_H-17 and regulatory T cells, respectively. Altered regulation of both transcription factors contributed to the phenotype of Irf4^−/− T helper cells. Our data position IRF4 at the center of T helper cell development, influencing not only T helper type 2 but also T_H-17 differentiation.