After encountering antigen, helper T (TH) cells undergo differentiation to effector cells, which can secrete high levels of interferon-γ, interleukin-4 (IL-4), IL-10 and other immunomodulators. How TH cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during TH-cell responses to foreign pathogens.