Autoimmune diseases primarily mediated by T-cells effect a significant proportion of the population and include common and distressing conditions such as diabetes, multiple clerosis, inflammatory bowel disease, skin diseases and arthritis. Current treatments are restrictive in terms of range of options and side-effect profiles and new drugs and new approaches are always eagerly sought. With the T-cell antigen receptor (TCR) as a model system we have identified a new approach to inhibit T-cell activation. By means of peptides derived from the transmembrane TCR-alpha chain region we have shown that T-cells, the major effector cells of disease, can be inhibited in vitro and the immune responses leading to disease ameliorated in animal models. The exact molecular mechanism of peptide action is still uncertain and assumed to involve a disturbance in transmembrane protein-protein interactions mediated by amino acid charges that disrupt normal signaling pathways. This chapter summarizes the results to date ofTCR core peptide (CP); the most effective peptide noted so far, in terms of function, behavior in membranes and future development and application as a therapeutic agent. The lessons learned from this model can be applied to other multi-subunit receptors that serve critical cellular functions and open new doors for drug design, development and application.