Vitamin D is now recognized as an important prohormone in health and disease. Its role in immunoregulation and cardiovascular and bone health has become topical in the lay press and the medical press in the past 5 yr. The target audience for this review includes the interested clinician and researchers. The prevalence of chronic kidney disease in the general population has further increased the interest and perhaps the applicability of findings of population studies. The basic physiology of vitamin D and receptor activation and biologic importance is reviewed, as well as various vitamin D analogues and nomenclature. Issues related to measurement of vitamin D and parathyroid hormone have the potential to complicate the clinical use of these tests and should be understood by all clinicians so as to ensure informed decision making and stimulate interest in participation in clinical trials. The epidemiology of vitamin D deficiency and supplementation in association with health status and disease status is reviewed, and issues related to association versus causation are highlighted. Some recommendations for pragmatic approaches and study design are suggested.