The elucidation of the metabolic pathway for vitamin D, including the delineation of the specific cytochrome P450s (CYPs) involved in activation and catabolism, has emphasized the overall importance of metabolic considerations in vitamin D analog design. This short review attempts to summarize recent findings with isolated CYPs and animal models in which CYPs are genetically manipulated to draw attention to structural features of vitamin D analogs that make them more or less resistant to metabolic enzymes. We conclude by placing metabolic considerations in the context of the other important aspects of vitamin D analogs.