The differentiation of naive CD4⁺ T cells into lineages with distinct effector functions has been considered to be an irreversible event. T helper type 1 (Th1) cells stably express IFN-γ, whereas Th2 cells express IL-4. The discovery and investigation of two other CD4⁺ T cell subsets, induced regulatory T (iTreg) cells and Th17 cells, has led to a rethinking of the notion that helper T cell subsets represent irreversibly differentiated endpoints. Accumulating evidence suggests that CD4⁺ T cells, particularly iTreg and Th17 cells, are more plastic than previously appreciated. It appears that expression of Foxp3 by iTreg cells or IL-17 by Th17 cells may not be stable and that there is a great degree of flexibility in their differentiation options. Here, we will discuss recent findings that demonstrate the plasticity of CD4⁺ T cell differentiation and the biological implications of this flexibility.