A prominent role for the execution of cell cycle and growth regulatory mechanisms within the three-dimensional context of nuclear architecture is becoming increasingly evident. Signaling pathways and regulatory networks that govern activation and suppression of genes controlling proliferation are functionally integrated for the organization and assembly of transcriptional machinery in nuclear microenvironments. The transcriptional activation of histone genes at the G1/S phase transition (S-point) is temporarily, functionally, and spatially distinct from transcriptional mechanisms at the restriction point (R-point). The spatial distinction in R-point versus S-point control is the localization of clustered histone gene loci at cajal bodies, which is modulated during the cell cycle. Histone nuclear factor P (HiNF-P), the principal factor mediating H4 histone gene transcription, is the final link in the signaling cascade that is initiated with growth factor dependent induction of cyclin E/CDK2 kinase activity at the R-point and culminates in the NPAT-mediated activation of histone H4 genes through HiNF-P at the G1/S phase cell-cycle transition.