At present, we only have indirect knowledge of the protective role of antigen-specific T cells in human viral infections, and it has been difficult to show a direct correlation between quantitative and qualitative measures of T-cell immunity and virus-associated diseases. However, as described in this Opinion article, recent advances in the characterization of T-cell functions and in the development of standardized T-cell assays have led to the identification of distinct functional signatures of T-cell responses that correlate with levels of viral replication and disease activity.