The treatment of disseminated melanoma with monotherapy and combined chemotherapy is still associated with rather low objective response rates and significant toxicity. Therefore, more effective substances and regimens with less toxicity are desired in the pharmacologic treatment of metastatic melanoma. The initial high expectations placed in systemic cancer treatment with interferons (IFNs) were not fulfilled, but IFN-alpha as a single substance revealed an objective response rate of 10% to 15% in melanoma patients. Clinical and experimental results suggest that the antitumoral activity of IFNs is mainly related to their antiproliferative effect, whereas immunomodulatory effects were not substantiated in clinical investigations. Results of in vitro trials showed that type-I IFNs may produce antagonistic effects combined with some agents (eg, cisplatin) and synergistic effects combined with others (eg, vindesine and BCNU). Clinical trials with combined IFN and cytostatic drug therapy were started a few years ago and have yielded promising initial results. Several studies with an entire number of more than 200 patients have already been performed to evaluate the combination of IFN-alpha and dacarbazine. This regimen was effective in over 50% of the patients, leading to complete or partial remissions in 27% and stabilization of the disease in an additional 28%. Toxicity is significant but still manageable, especially with a new generation of antiemetic drugs (serotonin receptor blockers). Several clinical trials performed so far did not find an improved efficacy by adding IFN-alpha to cisplatin or to vinblastine. The combination of IFN-alpha and vindesine seems to be more favorable and superior to the response rates of single agents and was well tolerated in an ongoing trial in our clinic. Recently, a new generation of multidrug combinations including IFN-alpha has been initiated and several reports with overall response rates greater than 50% have been published. In conclusion, combined regimens with IFN-alpha and different cytostatic drugs seem to be superior to treatments with cytostatic drugs alone and rather safe in disseminated melanoma. Additional combinations of IFNs and cytostatic drugs should be evaluated in future in vitro studies and in clinical trials.