Recent studies have demonstrated flexibility of the T-cell receptor (TCR) with respect to recognition of peptide bound to self major histocompatibility complex (MHC). With the introduction of peptide combinatorial libraries, it has become possible to dissect the extent of degeneracy in T-cell recognition. On the basis of these novel findings, Bernhard Hemmer and colleagues propose a conceptual framework for lymphocyte selection and survival and the occurrence of autoimmunity.