The proteins of the Runx gene family are among the most important transcription factors for regulating the differentiation and function of T lymphocytes. Runx1 and Runx3 are each involved in multiple and distinct steps throughout the process of T-cell differentiation. Targeted disruption or transgenic overexpression of the Runx genes causes pleiotropic and pathological phenotypes, including cell differentiation arrest, abnormal growth or survival, and immunological disorders. Runx proteins exert positive or negative effects on the transcription of a variety of possible target genes, depending on the context of the promoter, enhancer, and silencer. We now have a basic understanding of Runx function. To fully understand T-lymphocyte differentiation and function, the next challenge will be to investigate how Runx, as a member of a regulatory network, works in cooperation with TCR/cytokine receptor signaling and other transcriptionrelated factors.