The histone gene is a paradigm for transcriptional control at the G1/S phase transition point in the cell cycle. The histone gene promoter provides a blueprint for integration of regulatory signals which mediate responsiveness to factors controlling competency for cell cycle progression at the initiation of DNA replication. The downregulation of proliferation at the onset of differentiation is accompanied by and functionally linked to modifications in protein-DNA and protein-protein interactions at histone gene promoter regulatory elements. Chromatin structure, nucleosome organization and gene-nuclear matrix interactions facilitate crosstalk between regulatory sequences and targeting of transcription factors to cognate binding domains.