In 1986 we discovered that a murine monoclonal antibody, TEPC15 (T15), could bind to itself through homophilic affinity. Subsequently we located the region in T15 that is responsible for homophilic binding. Homophilic antibodies are infrequent as of today only four monoclonal homophilic antibodies have been described, but we found that homophilic polyclonal antibodies are in serum of normal mice and humans. The homophilic activity resides at the CDR3-FR4 region of the T15 heavy chain and a peptide of this sequence can confer the homophilic property to other antibodies using chemical and recombinant technologies. In vivo and in vitro studies have shown that men-made homophilic antibodies are more potent that their corresponding native antibodies. These findings suggest that homophilic antibodies could become a novel class of highly effective therapeutic drugs.