Skeletal development and bone remodeling require stringent control of gene activation and suppression in response to physiological cues. This chapter focuses on contributions by several indices of nuclear architecture to the control of gene expression in bone cells. It presents cellular, biochemical, molecular, genetic, and epigenetic evidence for linkages of developmental and tissue-specific gene expression with the organization of transcriptional regulatory machinery in subnuclear compartments. The fidelity of gene regulation necessitates the coordination of transcription factor metabolism and the spatial organization of genes and regulatory proteins within the three-dimensional context of nuclear architecture. Using skeletal genes as a paradigm, this chapter addresses mechanisms that functionally organize the regulatory machinery for transcriptional activation and suppression as well as cell fate and lineage commitment during skeletal development and remodeling. It also provides evidence for consequences that result from perturbations in nuclear structure: gene expression interrelationships that are associated with skeletal disease and tumors that metastasize to bone. Finally, it suggests that there is emerging recognition that the placement of regulatory components of gene expression must be coordinated temporally and spatially to facilitate biological control. The consequences of breaches in nuclear structure-function relationships are observed in an expanding series of diseases that include cancer and neurological disorders. © 2008 Elsevier Inc. All rights reserved.