Metastatic melanoma continues to be one of the most devastating of all cancers. It is a heterogeneous solid tumor whose treatment is challenging and difficult. It afflicts thousands of otherwise healthy patients annually, and clinicians have yet to discover an effective treatment for locally advanced disease. Over the years, much attention has been devoted to the development of an effective adjuvant treatment for patients with resected melanoma who remain at high risk for recurrence. The new advances in the understanding of melanoma's microenvironment and the complexity of its disease process, makes it clear that the treatment approach to this disease needs to be multi-directional. Numerous studies have tested various immunotherapeutic strategies in the treatment of advanced melanoma, in particular. These strategies include melanoma vaccines, interferon-alpha, interleukin-2 (IL-2), and dendritic cell vaccines. The Dr. Wallack's Surgery Research Laboratory has been studying melanoma vaccines for the past three decades. The first generation melanoma vaccine proposed by the Laboratory showed promising results in a subset of patients. Recently, the same Laboratory has produced a second generation melanoma vaccine (DC-Melvac) that consists of five human melanoma cell lines, a recombinant vaccinia virus that encodes for IL-2, as well as dendritic cells that have been programmed to recognize certain melanoma associated antigens. DC-MelVac was recently approved by the Food and Drug Administration for its use in Phase I clinical trials. These trials are expected to be underway in the near future. The ensuing review discusses many of the immunotherapeutic strategies that have been studied in the treatment of melanoma, including DC-MelVac.