The success of immunotherapy relies on the participation of all arms of the immune system and the role of CD4+ T lymphocytes in preventing tumor growth is now well established. Understanding how tumors evade immune responses holds the key to the development of cancer immunotherapies. In this review, we discuss how MHC Class II expression varies in cancer cells and how this influences antitumor immune responses. We also discuss the means that are currently available for harnessing the MHC Class II antigen presentation pathway for the development of efficient vaccines to activate the immune system against cancer.