Due to the development of genome-directed therapy and standardised methods of molecular analysis, molecular diagnostics has become an important part of daily practice in clinical oncology, especially in diseases like malignant melanoma where molecular testing has therapeutic implications. Melanoma has one of the highest mutation frequency of all cancers analysed in the TGCA (The Cancer Genome Atlas) and is characterised by an enormous genetic heterogeneity.1 The discovery of ‘driver mutations’ directly involved in melanomagenesis has led to the development of small-molecule kinase inhibitors. The emergence of BRAF and MEK inhibitors has completely changed treatment paradigm for BRAF-mutant metastatic melanoma with dramatically improvement of therapeutic outcomes. Despite high response rates, the duration of response remains limited, mainly due to the development of acquired treatment resistance. In this review the authors try to outline the importance of molecular oncology for malignant melanoma by giving an overview of the most frequent and potentially clinically relevant molecular alterations, the targeted therapies already used in clinical routine and by discussing the problem of acquired resistance and treatment strategies being developed to circumvent these obstacles.