Since dacarbazine was approved for treating metastatic melanoma in the 1970s, numerous studies have evaluated whether different schedules and dacarbazine-based combinations improve clinical outcomes. This evidence-based review shows that combining dacarbazine with other drugs having single-agent activity and/or hormonal or immunotherapeutic compounds fails to provide clinically meaningful improvements in survival, and may increase toxicity. In patients with metastatic melanoma, dacarbazine was previously administered in cycles of multiple consecutive daily infusions per cycle. The introduction of potent antiemetics, together with concerns relating to patient comfort and clinic utilisation time, has enabled regimens involving single-dose dacarbazine, administered at the same total dose per cycle. These appear to be as effective as multiple-dose schedules, are well tolerated, and are more straightforward to administer. Single-administration dacarbazine (850–1000 mg/m²), once every 3 weeks, is currently the standard reference therapy in patients with advanced melanoma. New effective therapies are urgently needed for this treatment-refractory disease.