Skin melanoma became one of the most frequent malignancies of the skin mainly due to the increased exposure to environmental UV irradiation. However, this did not lead to the increase of mortality, mainly due to the efficient early diagnostics as well as to the development of new therapies which were based on the identification of the mutation patterns and understanding of the immunobiology. Molecular markers are important to differentiate malignant tumors from precancerous ones but also routinely available to define prognosis. Immunotherapy can be used in any molecular class of melanoma, while target therapy is only available in case of BRAF mutant form. Meanwhile these novel therapies induce new resistance mechanisms based on the development of acquired genetic alterations. Due to these facts the initial molecular profiling of the resected primary tumors must gradually be replaced by continuous monitoring.