The role of medical treatment in advanced or metastatic malignant melanoma is still controversial, and there is no standard systemic therapy. Dacarbazine has been the most widely used single drug, despite its response rate range of 10-25%. A number of new drugs, polychemo-therapeutic regimens and combined modalities have been explored. Fotemustine, a new chloronitrosourea, is one of the most promising, and is active against disseminated malignant melanoma, in particular against brain metastases. Cisplatin has modest activity as single agent but positive results have been reported when it is combined with dacarbazine. Modulation of the activity of cisplatin and dacarbazine by tamoxifen has recently been postulated. The results of the few clinical trials in malignant melanoma are interesting but controversial. Interleukin-2 and interferon are active in this disease, but no more so than individual chemotherapeutic drugs. However, despite their high cost, combinations of immuno- and chemotherapeutic agents have been extensively investigated in order to evaluate possible synergisms. The above-mentioned efforts have produced contradictory results that are partly related to the difficulty in establishing whether a positive or negative treatment outcome is due to the chosen therapy or patient selection. For these reasons, patients with advanced malignant melanoma should be treated according to research protocols in specialized centers until an effective approach is developed.