The discovery of highly recurrent mutations in melanoma, such as BRAF(V600E), completely changed the clinical management including therapy of melanoma patients. In the era of Personalized Medicine targeted melanoma therapies showed high response rates, currently evidenced by BRAF inhibitors or immune-stimulating therapies. In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. In this regard, putative targetable biomarkers or those with predictive value for the outcome of currently applied therapies are promising tools for future precision oncology strategies. In addition, the progress made in genetic and epigenetic profiling technologies and their reconfiguration to real-time clinical screening approaches makes personalized medicine in melanoma an achievable objective in upcoming years.