We have made tremendous advances in the earlier diagnosis and treatment of melanoma. Indeed, the early recognition and surgical management of thin primary cutaneous melanoma of less than 1.00 mm in Breslow's thickness has resulted in a >97% cure rate. For stage III and IV disease, our current treatment options are poor, with response rates well below 20% and only rare long-term responders noted. This is most clearly highlighted in a recent review by Rosenberg et al. who examined the role of immunotherapy in the treatment of patients with stage IV melanoma over a nine-year period. Overall, 96% of all patients had metastatic melanoma, utilizing a wide array of vaccine strategies including synthetic peptides, naked DNA, dendritic cells (DC) and recombinant viruses in patients with various advanced malignancies. They found that the overall objective response rate, utilizing conventional oncologic criteria for clinical tumor response, was only 2.6%. By combining the results of the Surgery Branch with the latter trials above, a total of 1,306 vaccine treatments have been given for an overall objective response rate of 3.3%. Such dismal results compel us to take a critical look at our current approach to tumor immunology and immunotherapy, with the intention of improving our current understanding of the complex interactions that occur within the tumor microenvironment. This in turn will provide us with new insight and direction as we design the next generation of vaccines for patients with advanced cancer and in particular melanoma.