Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of clearly defined correlates of protection and the inherent difficulties that hinder full characterization of the determinants of successful T cell immunity in humans. Recent data from the disparate fields of infectious disease and tumor immunology have converged, with an emphasis on the functional attributes of individual antigen-specific T cell clonotypes, to provide a better understanding of CD8+ T cell efficacy. This new knowledge paves the way to the design of more effective T cell vaccines and highlights the importance of comprehensive immunomonitoring.