Metastatic melanoma is a deadly form of skin cancer. Extraordinary breakthroughs have been recently achieved in the treatment of the disease, leading to objective increase in patient survival. However, early detection of potential dangerous melanocytic lesions remains the best strategy to avoid metastatic dissemination, which is still the main cause of death in melanoma patients. In 2011, our team identified a germline mutation in microphthalmia-associated transcription factor ( ) that predisposes carriers to melanoma. Recently, we demonstrated that this mutation interfered with oncogene-induced senescence, one of the first events that should be overcome to allow melanoma development. Therefore, our works provide important clues on the early steps of melanomagenesis and as such might be useful for prevention or early therapeutic interventions in at risk-patients.