Recently treatment strategies in advanced malignant melanoma have significantly changed. Due to high response rates (e.g. more than 50% for the Dartmouth-regimen), combination chemotherapy has been the standard therapy in several oncological and dermatooncological centers in the USA and Europe. For the last three years different prospective randomized phase III trials failed to achieve similar results. There was no benefit in overall survival and in response duration in comparison to single agent chemotherapy. Currently, randomized clinical trials seem to be the best approach for the clinical treatment of metastatic melanoma. In this review several novel strategies against malignant melanoma are discussed with focus on the role of single agent chemotherapy and biochemotherapy.