Cell cycle progression into S phase requires the induction of histone gene expression to package newly synthesized DNA as chromatin. Cyclin E stimulation of CDK2 at the Restriction point late in G1 controls both histone gene expression by the p220(NPAT)/HiNF-P pathway and initiation of DNA replication through the pRB/E2F pathway. The three CDK inhibitors (CKIs) p21(CIP1/WAF1), p27(KIP1), and p57(KIP2) attenuate CDK2 activity. Here we find that gamma-irradiation induces p21(CIP1/WAF1) but not the other two CKIs, while reducing histone H4 mRNA levels but not histone H4 gene promoter activation by the p220(NPAT)/HiNF-P complex. We also show that p21(CIP1/WAF1) is less effective than p27(KIP1) and p57(KIP2) in inhibiting the CDK2 dependent phosphorylation of p220(NPAT) at subnuclear foci and transcriptional activation of histone H4 genes. The greater effectiveness of p57(KIP2) in blocking the p220(NPAT)/HiNF-P pathway is attributable in part to its ability to form a specific complex with p220(NPAT) that may suppress CDK2/cyclin E phosphorylation through direct substrate inhibition. We conclude that CKIs selectively control stimulation of the histone H4 gene promoter by the p220(NPAT)/HiNF-P complex.