Despite the limited efficacy of systemic chemotherapy in the treatment of metastatic melanoma, it remains the gold standard in the case of patients with a good performance status and no major comorbidities for whom radical surgery is unsuitable. Various drugs have been employed as monochemotherapy with response rates ranging from 0 to 20%. Many Phase III trials have compared the role of polychemotherapy with that of single-agent chemotherapy, or evaluated the impact of biological response modifiers alone or in combination with chemotherapeutic agents. However, the current scenario does not seem to be significantly different from the situation of 20 or 30 years ago. To date, no single drug, combination chemotherapy in addition to a hormonal or biotherapy compound, has demonstrated an overall survival benefit in a randomized clinical trial.