Among Europeans alone, a moderately high heritability of serum 25(OH)D levels (~50 to 70% for 25(OH)D) has been observed, as well as associations between 25(OH)D and several genetic polymorphisms in vitamin D metabolizing enzymes, although the functional consequences of these polymorphisms are not known. Small and large clinical trials among healthy individuals have also noted substantial inter-individual differences(as much as 5-fold) in the increases of serum 25(OH)D levels among participants given the same oral dose of vitamin D, the same minimal erythema dose (MED) of UV-B light, or the same dose of UV light. The importance of understanding inter-individual differences in vitamin D synthesis, metabolism and effect have been underscored by results from high dose randomized trials reporting that those in the vitamin D supplementation groups experienced a 31% higher bone fracture incidence, and significantly lower prostate cancer survival. There is a clear need to understand individual differences in the metabolism of vitamin D before future high dose trials proceed.