Metastatic melanoma remained for decades without any effective treatment and was thus considered as a paradigm of cancer resistance. Recent progress with understanding of the molecular mechanisms underlying melanoma initiation and progression revealed that melanomas are genetically and phenotypically heterogeneous tumors. This recent progress has allowed for the development of treatment able to improve for the first time the overall disease-free survival of metastatic melanoma patients. However, clinical responses are still either too transient or limited to restricted patient subsets. The complete cure of metastatic melanoma therefore remains a challenge in the clinic. This review aims to present the recent knowledge and discoveries of the molecular mechanisms involved in melanoma pathogenesis and their exploitation into clinic that have recently facilitated bench to bedside advances. 1. The Melanocytes: From Photoprotection to Cancer 1.1. Melanocyte Development Melanoblasts undifferentiated and unpigmented precursors migrate from the neural crest to their final destination, the epidermis and hair follicles, where they differentiate and become mature melanocytes able to synthesize and transfer melanin pigment to neighbouring keratinocytes (Figure 1). Melanocytes are also found in the stria vascularis of the inner ear cochlea where they are involved in the production of endolymph along with ion exchange essential for hearing. Melanocytes are also located in the iris and in the choroid where pigments are involved in the formation, behind the retina, of the darkroom, which is necessary for the vision. This review will focus on cutaneous melanocytes only. Figure 1: General overview of melanocyte physiology. Melanocytes derived from the neural crest in the form of undifferentiated and unpigmented precursors, the melanoblasts, migrate to their final destination, the epidermis, where they synthesize melanin in melanosomes. Pax3, Sox10, endothelin3 (ED-3) and its receptor (Endrb), c-Kit and Mitf play a critical role in the development of melanocytes. Melanin is then transferred to neighboring keratinocytes to ensure skin protection against the deleterious effect of ultraviolet radiation. During embryogenesis, the survival and migration of melanocytes rely on signaling pathways such as Wingless signaling (Wnt)/ -catenin, the endothelin B receptor and its ligand endothelin-3, the receptor tyrosine kinase KIT and its ligand KIT-ligand/SCF (stem cell factor), NOTCH [1, 2], and transcription factors activity such as paired box gene 3 (PAX3), SRY (sex-determining
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