Histone proteins are preferentially synthesized during the S-phase of the cell cycle, and the temporal and functional coupling of histone gene expression with DNA replication is mediated at both the transcriptional and posttranscriptional levels. The genes are transcribed throughout the cell cycle, and a 3-5-fold enhancement in the rate of transcription occurs during the first 2 h following initiation of DNA synthesis. Control of histone mRNA stability also accounts for some of the 20-100fold increase in cellular histone mRNA levels during S-phase and for the rapid and selective degradation of the mRNAs at the natural completion of DNA replication or when DNA synthesis is inhibited. Two segments of the proximal promoter, designated Sites I and II, influence the specificity and rate of histone gene transcription. Occupancy of Sites I and II during all periods of the cell cycle by three transacting factors (HiNF-A, HiNF-C, and HiNF-D) suggests that these protein-DNA interactions are responsible for the constitutive transcription of histone genes. Binding of HiNF-D in Site II is selectively lost, whereas occupancy of Site I by HiNF-A and -C persists when histone gene transcription is down regulated when cells terminally differentiate. These results are consistent with a primary role for interactions of HiNF-D with a proximal promoter element in rendering cell growth regulated human histone genes transcribable in proliferating cells.