Since the original approval of dacarbazine for the treatment of metastatic malignant melanoma, considerable effort has been expended in attempts to improve survival. This end point is the most unequivocal and ultimately meaningful for patients with cancer but has been one upon which clinical trials conducted to date have failed to demonstrate a meaningful impact. Little data regarding quality of life are currently available, but outside the setting of a clinical trial, a convenient single-agent dose regimen of dacarbazine is probably the best approach, currently. Targeted agents that are designed to abrogate various pathways implicated in signal transduction, cell cycle checkpoints, immunomodulation, and DNA repair offer promising novel approaches for the treatment of metastatic melanoma. However, cytotoxics may be essential backbones for combinations with these molecules. Phase II designs with targeted agents may require new and innovative end points to identify activity. The rational use of agents capable of abrogating drug resistance offers other opportunities for systemic chemotherapy that may then give rise to more rationally developed combinations.