Summary: Transcriptional regulation of T-cell development involves successive interactions between complexes of transcriptional regulators and their binding sites within the regulatory regions of each gene. The regulatory modules that control expression of T-lineage genes frequently include binding sites for a core set of regulators that set the T-cell-specific background for signal-dependent control, including GATA-3, Notch/CSL, c-myb, TCF-1, Ikaros, HEB/E2A, Ets, and Runx factors. Additional regulators in early thymocytes include PU.1, Id-2, SCL, Spi-B, Erg, Gfi-1, and Gli. Many of these factors are involved in simultaneous regulation of non-T-lineage genes, T-lineage genes, and genes involved in cell cycle control, apoptosis, or survival. Potential and known interactions between early thymic transcription factors such as GATA-3, SCL, PU.1, Erg, and Spi-B are explored. Regulatory modules involved in the expression of several critical T-lineage genes are described, and models are presented for shifting occupancy of the DNA-binding sites in the regulatory modules of pre-Tα, T-cell receptor β (TCRβ), recombinase activating genes 1 and 2 (Rag-1/2), and CD4 during T-cell development. Finally, evidence is presented that c-kit, Erg, Hes-1, and HEBAlt are expressed differently in Rag-2–/– thymocytes versus normal early thymocytes, which provide insight into potential regulatory interactions that occur during normal T-cell development.