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There has been substantial enthusiasm recently regarding the potential role of vitamin D in the primary and secondary prevention of cancer. Laboratory studies demonstrate a range of anticarcinogenic effects for vitamin D compounds, but human studies have yielded little consistent evidence supporting a protective association. Higher circulating levels of vitamin D (i.e., 25-hydroxyvitamin D or 25(OH)D) appear to be associated with reduced risk of colorectal and bladder malignancies, but higher risk of prostate and possibly pancreatic cancers, with no clear association for most other organ sites examined. Despite there being no official institutional recommendations regarding the use of vitamin D supplements for cancer prevention, screenings for vitamin D deficiency and vitamin D supplement use have increased substantially over the past decade. These widespread practices demonstrate that population sociobehavioral changes are often adopted before scientifically well-informed policies and recommendations are available. This review critically examines the currently available epidemiologic literature regarding the associations between circulating 25(OH)D, vitamin D supplementation, and vitamin D-related genetic variation and cancer risk and mortality, with a particular emphasis on prospective studies. We identify several important gaps in our scientific knowledge that should be addressed in order to provide sufficient reproducible data to inform evidence-based recommendations related to optimal 25(OH)D concentrations (and any role for vitamin D supplementation) for the primary and secondary prevention of cancer. With few exceptions, such recommendations cannot be made at this time.