CD4+ Th cells are responsible for orchestrating diverse, pathogen-specific immune responses through their differentiation into a number of subsets, including T H 1, T H 2, T H 9, T follicular helper, T follicular regulatory, and regulatory T cells. The differentiation of each subset is guided by distinct regulatory requirements, including those derived from extracellular cytokine signals. IL-2 has emerged as a critical immunomodulatory cytokine that both positively and negatively affects the differentiation of individual Th cell subsets. IL-2 signals are propagated, in part, via activation of STAT5, which functions as a key regulator of CD4+ T cell gene programs. In this review, we discuss current understanding of the mechanisms that allow IL-2–STAT5 signaling to exert divergent effects across CD4+ T cell subsets and highlight specific roles for this pathway in the regulation of individual Th cell differentiation programs.