Adaptive immune responses and immunopathogeneses are based on the ability of T cells to respond to specific antigens. Consequently, understanding T-cell recognition patterns in health and disease involves studying the complexity and genetic heterogeneity of the antigen recognition pathway, which includes both T-cell receptors and the antigen-presentation machinery. In this Perspective, we overview the development and use of technologies for assessing T-cell recognition in a clinical context, and discuss how knowledge of T-cell recognition pathways can be critical before, during and after disease treatment. The ability to assess T-cell-mediated immunity in individual patients during disease progression might enable the identification of patient-specific biomarkers that predict therapeutic efficacy and response. Effective strategies for the complex analysis of T-cell specificity in clinical settings are highly desirable and could complement current approaches for the monitoring of therapy responses.