The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognising virtually any pathogen. It has been known for several decades that T lymphocytes recognise short peptides derived from degraded proteins that are presented by major histocompatibility complex (MHC) molecules. Nonetheless, the molecular basis of this interaction is still a matter of debate, the central issue being the roles played by the complementarity-determining regions (CDR) in this context. In this study we have generated a transgenic mouse line lacking all three TCR-β chain CDR loops and a second line lacking the hypervariable CDR3 loop only. This project is the first attempt to characterise such transgenic mice, which were found to develop normally and to generate functional T lymphocytes. We demonstrate that in this murine TCR-β transgenic system, CDR-modified thymocytes can be selected on MHC and develop into functional peripheral T cells. We show for the first time that T cells lacking all three TCR-β chain CDR loops respond to protein antigen in an MHC-restricted manner. This will provide insight into the structural basis of the TCR-MHC-peptide interaction and increase our current knowledge of the requirements for the selection and functionality of MHC-restricted T cells.