Naïve CD4⁺ T cells are educated in the thymus to survey the periphery for cognate antigen while ignoring self or commensal antigens. T cell antigen receptor (TCR) cross-linking initiates signaling cascades that integrate information from co-stimulatory receptors and locally available cytokines to chart the course of inflammation. The dynamic composition of transcription factors acting within a given T cell drive clonal expansion and specify differentiation into a growing array of effector and regulatory T cell subsets. The classical γ-interferon (IFNγ)-secreting T helper type (Th)-1 and IL-4-producing Th2 cell subsets utilize T-bet or GATA3 as master lineage regulators. It is now understood that naïve T cells also differentiate into pro-inflammatory Th17 or tissue-protective inducible T regulatory (iTreg) cells under the respective guidance of RORγt or FOXP3. Emerging data highlight the reoccurring theme that these Th17 and iTreg master regulators prescribe T cell lineage commitment through interactions with each other, as well as with a broader network of auxiliary transcription factors.