The vitamin D endocrine system plays a primary role in the maintenance of calcium homeostasis as well as exerting a wider range of biological activities including the regulation of cellular differentiation and proliferation, immunity, and reproduction. Most of these latter activities have been demonstrated using in vitro techniques. A major issue is to place such in vitro findings into their physiological context. Vitamin D exerts its genomic effects through a nuclear gene transcription factor, the vitamin D receptor (VDR), while metabolism of vitamin D both to its biologically active form, as well as to its excretory product, plays a major role in determining biological activity at the tissue level. Considerable information has become available recently concerning the metabolism of vitamin D both in the kidney and in non-renal tissues. These data confirm the endocrine action of vitamin D through renal metabolism which provides 1,25 dihydroxyvitamin D (1,25D) to the circulation. The major organ responding to the endocrine action of 1,25D is the intestine where it controls absorption of calcium and phosphate. Preliminary information regarding the contribution of tissue-specific production of 1,25D to its paracrine/autocrine activity is now becoming available. In bone cells, these data provide evidence for the modulation of cell proliferation and stimulation of bone cell maturation. The relevance of these concepts to the clinical laboratory is discussed in the context of vitamin D insufficiency and the increased risk of hip fracture amongst the elderly.