Prostate cancer is a deadly disease that is in drastic need of new treatment strategies for late stage and metas-tatic prostate cancer. Immunotherapy has emerged as a viable option to fill this void. Clinical trials have been conducted that induce tumor clearance through cytotoxic T lymphocyte (CTL) activation, these studies have had mixed outcomes with the overlying problem being the lack of a complete immune response with sustained killing and the formation of tu-mor specific memory cells. To overcome this, we have outlined the need for activating the HLA class II pathway in induc-ing a sustained CD8+ T cell response and the development of effective memory. We have also discussed the ability of prostate cancer cells to express stable HLA class II molecules that can be manipulated for tumor antigen (Ag) processing and presentation. This review also sets to outline new directions that exist for the use of class II-restricted Ags/peptides in devising cancer vaccines as well as combined chemoimmunotherapy. A better understanding of these concepts will im-prove future cancer vaccine studies and further the field of cancer immunobiology.