Deep sequencing of T-cell receptors enables the comprehensive profiling of lymphocyte populations and the characterization of the repertoire of T-cell responses against tumors, which could be applied to diagnose cancers. Ostmeyer and colleagues introduce a novel approach to characterize TCR patterns correlating with antigen recognition. By projecting the large TCR sequence space into a handful of biophysicochemical descriptors for key residues and seeking TCRs with similar antigen-binding capabilities even in the absence of identical amino acids, this approach presents several advantages over current methods.See related article by Ostmeyer et al., p. 1671.