The response of T cells to antigen shows an amazing degree of both sensitivity and specificity, with a cell responding to 1-10 peptide-MHC complexes and being sensitive to single amino acid substitutions. Kinetic proofreading or feedback pathways achieve specificity at the level of the receptor, whereas serial engagement of receptors by ligand molecules enhances sensitivity. Crosstalk between receptors, integration of signals and/or tuning of responses is important at the level of the cell. Induction of anergic or regulatory cells by suboptimal stimuli prevents cell activation by multiple encounters with weak ligands. Thus, for optimal sensitivity and specificity, it is necessary to have mechanisms that operate at the level of the receptor, the cell and finally, the population of responding cells.