Traditionally, immunology is mainly about the study of the immune response against foreign antigens, such as bacteria and viruses. Accordingly, tumor cells expressing alien or altered antigens make the attractive targets against which cancer immunology is initiated. However, recent comprehensive studies demonstrated that most prevalent antigens recognized by our immune system in cancer are those shared, nonmutated self-antigens expressed also by normal tissue cells. Thus, how to break the self-tolerance and avoid the concomitant autoimmunity remain the two challenges in cancer immunology. Dendritic cells (DCs) are the most effective antigen-presenting cells. They are capable of capturing, processing, and presenting antigens to T- and B-cells. This feature targets dendritic cells as the ideal candidates for breaking self-tolerance in cancer immunology. Clinical trials have demonstrated that dendritic cells are effective messengers. They circulate around the body and stimulate cytotoxic T-lymphocytes to clear tumor cells. Vaccination with DCs led to a clinical response in patients with melanoma, specifically those without significant autoimmunity. In this paper, we will examine the strategies and efficacies of DC-based vaccinations in the treatment of patients with melanoma.