Numerous in vitro and in vivo observations, demonstrating that 1,25-dihydroxyvitamin D3 is a potent inhibitor of tumor cell growth, provided the rationale for using this seco-steroid hormone to treat patients with leukemia and various types of cancer. However, the therapeutic efficacy of systemically applied vitamin D analogs for treating cancer has not yet fulfilled its promise. A main reason for these disappointing results is that the use of systemically applied vitamin D analogs is limited by severe side effects, mostly hypercalcemia, at the supraphysiological doses needed to reach clinical improvement. New concepts for the development of cancer treatment strategies that are based on the use of vitamin D3 compounds are discussed in this manuscript. At the moment, different strategies that may enable the application of vitamin D analogs for the treatment of various malignancies, including malignant skin tumors, are employed. It has been shown that certain vitamin D analogs differ in their intracellular metabolism, nongenomic actions, pharmacokinetics, interaction with the vitamin D binding protein (DBP) or the vitamin D receptor (VDR). Several of these new concepts are based on recent laboratory results demonstrating that VDR requires heterodimerisation with additional nuclear cofactors such as the retinoid-X receptor (RXR) for sufficient DNA-binding or are based on new findings in the metabolism of vitamin D. Taken together, these new strategies hold promise that analogs of 1,25-dihydroxyvitamin D3 may herald a new era in the treatment of various malignancies, including skin cancer.