The active metabolite of vitamin D3 - 1,25-(OH)2D3 - exerts most of its physiological and pharmacological actions through its nuclear receptor (VDR), regulating the transcriptional machinery of a variety of cell types. Basic research motivated by the detection of VDR in numerous target cells, has indicated potential therapeutic applications of VDR ligands in osteoporosis, cancer, secondary hyperparathyroidism and autoimmune diseases such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. In recent years vitamin D analogs, particularly calcipotriol and tacalcitol, have been used as topical therapeutic agents in vitiligo, an autoimmune pigmentary disorder characterized by aberrant loss of functional melanocytes from involved epidermis. The presence of cytotoxic T cells targeting melanocyte antigens and imbalance of the cytokine network were described as characteristics of the disease, eventually leading to melanocyte damage and death. Vitamin D ligands are designed to target the local immune response in vitiligo, acting on specific T cell activation, mainly by inhibiting the transition of T cells from early to late G1 phase and by inhibiting the expression of several pro-inflammatory cytokines genes, such as those encoding tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). Vitamin D3 compounds are known to influence melanocyte maturation and differentiation and also to up-regulate melanogenesis through pathways activated by specific ligand receptors, such as endothelin receptor and c-kit. In this review we summarize the complex pathogenetic rationale of vitamin D analogs in vitiligo depigmentation. Understanding the cellular and molecular mechanisms through which vitamin D targets the epidermal melanin unit is of great interest for identification of new effective therapeutic combination(s) that might induce repigmentation in vitiligo.