A vaccine is typically defined as any preparation used as a preventive inoculation to confer immunity against a specific disease. Vaccines for infectious diseases are highly effective, acting by inducing antigen-specific immunity that prevents subsequent infection. Unfortunately, the success of vaccines in infectious diseases has not been mirrored in oncology. This failure is the result of several challenges facing cancer vaccines, including the conceptual shift from disease prevention to disease treatment, tumor-induced immunosuppression and other mechanisms of immune escape, the similarity between tumor antigens and self antigens to which the patient is tolerant, unfavorable effector-to-target ratios in patients with established tumors, and financial and regulatory issues. Despite this, cancer remains a promising target for vaccine therapy. Melanoma in particular is known for its inherent immunogenicity on the basis of many anecdotal reports of spontaneous immune-based tumor regression, and thus has been the focus of immunotherapeutic approaches. Rare but significant vaccine-induced clinical regression of melanoma has spurred intensive investigations to augment vaccine efficacy. This review explores the many vaccine strategies that have been clinically tested for the treatment of melanoma and considers future approaches of cancer immunotherapy.