The molecular rules that govern MHC restriction, and allow T‐cells to differentiate between peptides derived from healthy cells and those from diseased cells, remain poorly understood. Here we provide an overview of the structural constraints that enable the T‐cell receptor (TCR) to discriminate between self and non‐self peptides, and summarize studies that have attempted to correlate the biophysical parameters of TCR/peptide–major histocompatibility complex (pMHC) binding with T‐cell activation. We further review how the antigenic origin of peptide epitopes affects TCR binding parameters and the ‘quality’ of a T‐cell response. Understanding the principles that govern pMHC recognition by T‐cells will unlock pathways to the rational development of immunotherapeutic approaches for the treatment of infectious disease, cancer and autoimmunity.