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.