The success of immunotherapy in the treatment of cancer patients has proved the long-standing hypothesis that endogenous adaptive immune responses against the tumor can be harnessed to mediate protection by immune checkpoint blockade. This approach has shown impressive control of disease and improved survival in up to 50% of patients with certain tumors. Genetic and immune analysis of human cancers suggests that one mechanism of resistance to immune checkpoint blockade may be due to lack of tumor-specific T cells. In principle, vaccines have the potential to overcome this defect by either expanding low-level existing tumor-specific T cell responses or priming tumor-specific T cells. Recent advances in next-generation sequencing have improved our understanding of defining cancer antigens. Application of this will require vaccine delivery approaches that can induce potent and broad T cell immunity in an efficient manner for personalized therapy. This Keystone Symposia conference will highlight recent insights in the characterization of immunogenic cancer antigens, the biology and underlying mechanisms of T cell priming, and the development of novel approaches designed to expand T cell responses. Part of the meeting will also be devoted to the development of technologies to monitor T cell responses in response to immune interventions.