The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the twentieth anniversary of the first descriptions of the cytokine signals that promote the differentiation of interleukin-9 (IL-9)-secreting T cells, this Review focuses on the extracellular signals and the transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease, and we propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.