There is much renewed activity in the testing of vaccines that target metastatic melanoma, driven by successes in other areas, most notably prostate cancer. Yet, sound evidence that any stand-alone vaccination approach has clinical benefit against melanoma remains lacking. With phase III studies showing no efficacy of promising whole-cell vaccines and heat shock proteins, peptide and dendritic cell vaccines remain the most common approaches. A major obstacle to progress is the lack of any surrogate measures in phase II studies that associate meaningfully with clinical benefit, and this is further complicated by phase III evidence in prostate cancer that immunologic monitoring, tumor response rates, or even times to tumor progression may not accurately predict survival benefit. The area with the most progress has been in combining vaccines with other systemic immunostimulatory agents. Although no vaccine has been found which fulfills the prediction from murine models that they can enhance the efficacy of ipilimumab, combining a peptide vaccination with high-dose interleukin 2 was shown to enhance complete and overall response rates compared with interleukin 2 alone. These promising combinations continue to struggle with the same unresolved issues that have plagued melanoma vaccines from the beginning-what are the best antigens to target, what are the best methods of vaccination, and what constitutes a sufficient immune response to be of value? Virtually no progress has been made toward answering these questions.