Even early clinical studies showed that adjuvant chemotherapy achieved no therapeutic benefit for melanomas so that in the current guidelines its use is only recommended within the framework of clinical studies. For over 30 years interferons have been used in the adjuvant treatment of primary high risk melanomas as well as in the treatment of metastasized melanomas. They function in an antiviral, immune modulating and antitumor fashion. Direct and indirect effects on tumor cells could be demonstrated for interferons. In Europe low dosage interferon therapy is approved and has become widely established for stage II melanomas, whereas in the USA high dosage therapy for stage III and since March 2011 therapy with pegylated interferon in stage III are also approved. In this article the most important study results will be dealt with in detail. In summary, according to the current study situation therapy with interferon should be offered especially to patients with ulcerated primary melanoma and microscopic lymph node infiltration. Many attempts have been made in the last decades to positively influence the survival time of distant metastasized melanoma by systemic therapy. The recent development of the antibody ipilimumab against cytotoxic T-lymphocyte protein 4 (CTLA-4) could show for the first time a survival advantage in the therapy of melanoma patients in advance stage disease. The licensing of ipilimumab has meant that there is now a new standard available for the second line therapy of malignant melanoma which will be included in the guidelines on therapy of malignant melanoma. A further interesting option for adjuvant therapy is currently vaccination with the recombinant melanoma-associated protein 3 (MAGE-A3) protein in combination with the adjuvant AS015.