The emergence of Th17 cells as a distinct subset of effector CD4 T cells has led to a revised model of the adaptive immune system. Whereas the Th1-Th2 paradigm revolutionized our understanding of adaptive immunity by introducing the concept of alternative developmental pathways for naïve CD4 T cells induced by distinct cytokine cues from microbe-activated innate immune cells, delineation of Th17 cell differentiation has extended this concept and has led to a greater appreciation of the developmental plasticity of CD4 T cells. In contrast to Th1 and Th2 cells, which have been thought to represent terminal products of their respective developmental programs, recent studies suggest that Th17 cells are less rigid. In addition to early developmental links to induced regulatory T cells (Tregs) reflected in the shared requirement for TGF-β, it is now apparent that there is substantial plasticity late in the Th17 program, which allows committed Th17 cells to transition from effectors that produce predominantly IL-17A and IL-17F, to effectors that produce predominantly IFNγ. Tregs appear to have similar plasticity. This promises new insights into strategies for balancing antimicrobial defense with restraints on immune-mediated tissue injury, and raises new questions regarding the stability of epigenetic modifications that accompany induction of cytokine gene expression during T cell lineage development. © 2009 Elsevier Ltd. All rights reserved.