T cell recognition of antigen is a crucial aspect of the adaptive immune response. One of the most common means of pathogen immune evasion is mutation of T cell epitopes. T cell recognition of such ligands can result in a variety of outcomes including activation, apoptosis and anergy. The ability of a given T cell to respond to a specific peptide–MHC ligand is regulated by a number of factors, including the affinity, on- and off-rates and half-life of the TCR–peptide–MHC interaction. Interaction of T cells with low-potency ligands results in unique signaling patterns and requires engagement with a larger number of T cell receptors than agonist ligands. This review will address these aspects of T cell interaction with weak ligands and the ways in which these ligands have been utilized therapeutically.