To treat malignant melanoma successfully currently means to recognize the tumor at an early stage and to remove it immediately. Aside from individual cases, available treatment modalities are not able to increase survival, especially in the palliative situation. Thus innovative experimental approaches are urgently needed to strongly improve the palliative and adjuvant treatment of melanoma. Anti-tumor effects are expected from targeted therapies, which are directed against defined molecules decisive for tumor pathogenesis. Crucial points of attack are signaling pathways, angiogenesis and apoptosis resistance. New diagnostic and therapeutic developments have enhanced the efficacy of chemotherapies. Increasing insights into tumor immunology provide new treatment approaches of vaccination, cell transfer and especially of blocking immune tolerance mechanisms. It will be challenging for the future to identify and characterize more precisely those patients who might most benefit from a certain treatment approach.