The ability of the immune system to distinguish between self- and nonself antigens is controlled by mechanisms of central and peripheral tolerance. Although the induction and maintenance of tolerance is important for preventing autoimmunity, breaking self-tolerance is a crucial constituent for combating cancers. Cancer patients are able to develop spontaneous immune responses to tumors that they bear, however these responses are not suboptimal for eradicating tumors. Moreover, none of the current immune strategies is able to activate the immune system to respond against tumor cells as it responds against infectious agents. These observations have raised the question of how to activate immunity in cancer patients to a threshold required for tumor rejection. Because tolerance is emerging as a central obstacle for immune recognition of human tumor antigens, this chapter describes how T- and B-cells are generated and activated in the periphery. It also outlines the technical advances in tumor antigen discovery and validation.