Despite intensive clinical and research efforts during the last decades the prognosis for patients with stage IV melanoma still remains fatal. An efficient adjuvant treatment for patients with a high risk of relapse and metastases is one of the most urgent fields in clinical research. Systemic adjuvant chemotherapy was not beneficial in terms of relapse-free or overall survival improvement in several clinical trials. Treatment with IFN-α-2a and -2b treatment was the first and as yet only adjuvant therapy which has been proven to show a benefit in controlled studies and to gain approval in Germany in the indications for adjuvant therapy. Current clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon and on the other hand on testing new compounds, such as the CTLA4 inhibitor ipilimumab or a vaccination against the MAGE-A3 peptide.