The overall median survival of patients with systemic metastasis from melanoma is about 6 months. Survival is dependent on the sites of first metastasis, the resectability of the metastases, and the number of metastases. Patients with non-visceral metastases at first relapse i.e. in skin, subcutaneous tissues, distant lymph nodes, and lung, have a better survival rate than patients with visceral (liver, bone, brain) metastases. Treatment of patients with systemic melanoma should include careful evaluation for the potential role of surgery, radiotherapy, and systemic therapy. The main use of chemotherapy in metastatic melanoma patients remains palliative. The chapter reviews the chemotherapeutic options available for the treatment of malignant melanoma including recent published works on new agents, multi-agent therapy, high dose chemotherapy with autologous bone marrow rescue, adjuvant chemotherapy and regional perfusion chemotherapy.