Osteocytes are derived from osteoblast precursors during bone mineralization. Entombed cells play complex roles in bone remodeling; responsiveness to physiologic stimuli; and mineral homeostasis. Both the differentiation and mature cell functions of the osteocyte are regulated by systemic hormones including 1,25(OH)2D3 and PTH, growth factors and inflammatory cytokines, and mechanical stimuli. Neither the underlying epigenetic changes that occur to the genome nor the patterns of transcription factor binding that accompany assumed changes in gene expression during differentiation are known. We recently used the murine IDG-SW3 osteoblastic cell line and its progression to the osteocyte phenotype to explore these issues in detail. Changes in gene expression that occurred during differentiation were first examined using RNA-seq analysis. We then coupled these changes to genome-wide epigenetic histone modifications that mark promoters, transcription units and regulatory regions of annotated genes, and to changes in basal binding of transcription factors such as RUNX2 and C/EBPβ. Finally, we examined the ability of 1,25(OH)2D3 and PTH to promote changes in gene expression during early and late stage osteocytogenesis and to facilitate global VDR/RXR and CREB binding to the genome. As expected, numerous changes in gene expression were noted during differentiation, although it is clear that the osteocyte is osteoblast-derived. GO term analysis indicated that gene networks in both cell types included ossification, apoptosis, vasculature development, and immune response. The histone marks identified across the genome correlated directly with the structural and functional features of regulated genes and pinpointed the presence of extensive regulatory regions; these also exhibited significant changes during the differentiation process. That these regions were regulatory in nature was confirmed through frequent occupancy by RUNX2 and/or C/EBPβ at these sites. Finally, regulatory regions of genes marked by H3K4me1, H3K9ac and H3K927ac and responsive to either 1,25(OH)2D3 or PTH frequently showed an accumulation of VDR/RXR or CREB, respectively. Genes in this class included Spp1, Mmp13, Vdr, Sp7, Tnfsf11, Runx2, Meis2, and also others. Our studies provide new insight into osteoblast to osteocyte differentiation and the responsiveness of these cell types to hormones at the genomic level.