In line with the role of T cells as critical mediators of the adaptive immune response, recombinational and junctional diversity of the T cell receptor makes each T cell almost entirely unique. Therefore, it makes sense that T cells also display enormous phenotypic and functional diversity in both blood and tissues. This is particularly evident in the context of both infectious disease and cancer, where a great deal of heterogeneity is observed both within individual patient tumors and between patients. A major goal of the lab is to understand the roles of antigen specificity in shaping the heterogeneity of T cells. Here I will talk about our efforts using mass cytometry and single-cell sequencing to identify and profile various antigen-specific T cell populations to gain insights about the boundaries that their specificities place on their capacity to differentiate and take on various phenotypic and functional profiles. For instance, I will describe the implications and hypotheses that come from our recent work in identifying and profiling T cells that are specific for cancer-unrelated antigens and that we designate as bystander T cells. Overall, I hope to highlight the utility of combining broad cellular immune profiling with the analysis of antigen-specific T cells to gain insight about immunological mechanisms of immunity to infectious disease or cancer in humans.