Melanoma is considered a chemotherapy-resistant cancer, but in reality there are several chemotherapy drugs with significant single-agent activity. Response rates to combination regimens are reproducibly higher than with standard dacarbazine, but of the randomized trials comparing combination regimens with dacarbazine, none were of sufficient size to detect a realistic effect on survival. Similarly, adjuvant chemotherapy has not had a realistic test in melanoma. Response to chemotherapy is associated reproducibly with better survival rates suggesting that regimens with higher response rates are needed. Recent observations suggest that combining antiangiogenic agents with either dacarbazine or temozolomide can double response rates. These combinations are worthy of further investigation and might serve as a foundation on which to build a combination regimen that improves overall survival in metastatic melanoma patients.