Vitamin D is a principal modulator of skeletal gene expression, thus necessitating an understanding of interfaces between the activity of this steroid hormone and regulatory cascades that are functionally linked to the regulation of skeletal genes. Physiologic responsiveness requires combinatorial control, whereas co-regulatory proteins determine the specificity of biologic responsiveness to physiologic cues. It is becoming increasingly evident that regulatory complexes containing the vitamin D receptor are dynamic rather than static. Temporal and spatial modifications in the composition of these complexes provide a mechanism for integrating regulatory signals to support positive or negative control through synergism and antagonism. Compartmentalization of components of vitamin D control in nuclear microenvironments supports the integration of regulatory activities, perhaps by establishing thresholds for protein activity in time frames that are consistent with the execution of regulatory signaling.