The diverse biological actions of the vitamin D hormone 1, 25-dihydroxyvitamin D3 (1, 25 (OH) 2D3) that are beyond its contribution to the maintenance of mineral metabolism are now well recognized (1). These actions include significant roles in skin maturation, protection, and function, the immune system, cardiovascular activity, neuromuscular function, bile acid metabolism, xenobiotic detoxification, muscle activity, and hepatic function (2). They also include broad cellular growth control mechanisms that include blockade of proliferation, prodifferentiation, induced apoptosis, and other fundamental cellular processes that may be of therapeutic relevance in cancer (3). Many of these activities have been described over a span of several decades both in cultured cells of specific lineage origin and in vivo. In the latter case, these studies have made frequent use of genetic strains of mice that are either globally or tissue specifically deficient in the expression of the vitamin D receptor (VDR), the central mediator of vitamin D action in all tissues (2, 4, 5). Perhaps most importantly, the beneficial biological effects of vitamin D in many of these systems appear to have translational and clinical components as well, because clinical pathologies associated with these systems frequently correlate with vitamin D deficiency, and at least, a subset have been shown to respond positively to increased vitamin D intake (6). Accordingly, the actions of 1, 25 (OH) 2D3 in many of these tissues in humans are generally not in dispute. The mechanism through which vitamin D acts in tissues centers on the presence and activity of the VDR, a transcription factor that is activated by hormonal vitamin D and functions at the level of the genome in a cell-specific manner to regulate the transcription of genes (5). This receptor is highly expressed in tissues, such as intestinal epithelial cells and proximal and distal tubules of the kidney, and mesenchymal lineage cells, such as chondrocytes, early osteoblast precursors, mature osteoblasts, and osteocytes, and in many other cell types as well (7). Molecularly cloned and the protein product studied over several decades, many of the principles of the VDR’s modulatory actions to regulate the expression of specific genes are now well established, most recently at the genome-wide level (8–11). Although not fully understood, our advanced appreciation of the mechanisms through which the VDR operates at the genetic level stands in stark contrast to those that have been proposed to account for the so called rapid, nongenomic actions of the hormone, where the VDR or other “receptors” have been suggested to regulate specific membrane-associated activities in cells (12). Despite suggestions to the contrary, both the mechanisms that underlie these latter activities and their relevance in vivo remain to be determined, although considerable mechanistic precedent has been established for nongenomic activity through the study of nuclear receptors for estrogen, the androgens, and progesterone. With these issues in mind, it is not surprising that studies aimed at understanding the actions of the vitamin D hormone in such tissues as the nervous system, the cardiovascular system, and the skeletal muscle system have focused upon detection of the VDR as an initial prerequisite for defining a direct mechanism of action of the hormone in these systems. Although this may appear to the outsider to be a relatively easy task, the VDR protein is expressed at extremely low levels and thus is not easily detected even in bone fide vitamin D-sensitive target tissues. Therefore, it is even more difficult to identify the receptor in atypical tissues where VDR abundance may be …