Low vitamin D status has been associated with increased risk of several cancers and obesity; concurrently, obesity and cancer have been linked to impaired vitamin D status. In both cancer and obesity, selective elimination of cancer cells and adipocytes can result in decreasing tumor size and a long-term reduction in adipose tissue mass. These effects can be achieved through induction of apoptotic cell death. The vitamin D-derived hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in epithelial cancer cells and mature adipocytes via induction of apoptotic Ca2+ signal - a sustained, prolonged increase in concentration of intracellular Ca2+. This Ca2+ signal functions as an apoptotic initiator that directly recruits apoptotic effectors, Ca2+-dependent proteases, in cancer cells and adipocytes. The 1,25(OH)2D3 - cellular Ca2+ - apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2+ and Ca2+-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and obesity. The concept of maintaining an increased vitamin D status for protecting against cancer and decreasing adiposity also warrants further evaluation.