Over the last century, vaccine studies have demonstrated that the human immune system, with appropriate help, can limit or prevent infection against otherwise lethal pathogens. Encouraged by these results, success in animal models and numerous well-documented reports of immune-mediated melanoma regression in humans, investigators developed melanoma vaccines. However, despite considerable laboratory evidence for vaccine-induced immune responses, clinical responses remain poor. Recent studies have elucidated several mechanisms that hinder or prevent the creation of successful vaccines and suggest novel approaches to overcome these barriers. Unraveling the mechanisms of autoimmunity, dendritic cell activation, regulatory T cells and Toll-like receptors will generate novel vaccines that, when used in conjunction with standard adjuvant therapies, may result in improved clinical outcomes. The objective of this review is to provide an overall summary of recent clinical trials with melanoma vaccines and highlight novel vaccine strategies to evaluate in the near future.