Since discovery of the first melanoma-associated tumor antigen, great strides have been made in elucidating the cellular and molecular basis for the adaptive immune response to human cancers, including melanoma. Despite this understanding and its application to melanoma patients in the form of various tumor vaccines, advanced-stage melanoma continues to be a devastating disease, associated with significant morbidity and mortality. Recent advances in melanoma immunotherapy and novel T-cell co-stimulation-based strategies that have shown promise in preclinical studies are discussed. While many current antigen-based approaches, either in the form of active or passive immunotherapy, may generate a tumor-specific T-cell response, the overall response rate observed clinically in most cohorts of melanoma patients has been suboptimal. Therefore, antigen-independent strategies capable of overcoming barriers to tumor eradication, such as tumor-mediated suppression, tumor evasion or self-tolerance, may represent promising new additions to the current arsenal of tumor vaccines.