The activation of T lymphocytes is initiated by the binding of MHC-peptide complexes on antigen-presenting cells to MHC-restricted, peptide specific TCRs. Significant progress has recently been made in understanding the structure of the TCR and in the direct quantitative examination of the primary binding interactions between MHC-peptide complexes and the TCR. Attempts to develop quantitative models for the differential activation of T cells by MHC-peptide ligands that differ subtly in their structure have largely been based on either the affinity of the MHC-peptide complexes for the TCR in question or on the dissociation kinetics of the MHC-peptide complex from the T cell.