© 2017 USCAP, Inc All rights reserved. Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH) 2 D3, or through the action of CYP11A1 to produce mono-di-and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORÎ 3. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH) 2 D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORÎ 3 expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.