In recent decades our understanding of immune cell activation and homeostasis has significantly expanded. Such progress helped to better define the cellular, molecular, and epigenetic networks involved in the immune response in the tumor microenvironment and renewed the enthusiasm towards the potential power of cancer immunotherapy. However, successful translation of novel mechanistic discoveries into effective immunotherapy was hindered by a number of obstacles, among them the ability of tumors to tolerize host lymphocytes rendering them functionally incompetent and the tumor's ability to evade antigen-specific immune recognition through a variety of genetic, epigenetic, and stromal factors. These immunosuppressive strategies have, thus far, blunted our efforts to effectively unleash anti-cancer immunity. Fortunately, the wealth of new information regarding the interactions between tumors and the immune system and the regulation of certain highly antigenic tumor proteins has led to novel approaches with the potential to render cancer cells helpless towards immune attack. Here we summarize recent findings on cancer-induced T-lymphocyte tolerance and discuss a novel "vaccinate-induce" strategy conceived to counteract these effects at an epigenetic level.