This review recalls the history of homophilic antibody discovery and adaptation for cancer immunotherapy. Homophilic antibodies are a rare type of murine monoclonal antibody produced by plasmacytomas. They are self-binding in solid-phase assays and, in solution, are in an equilibrium of monomers and dimers. This equilibrium is controlled by antibody concentration and temperature, whereby low concentration and high temperature promote dimerization. The antibody domain that induces homophilic binding resides in the Vh region of the prototype T15 antibody. A peptide representing this domain can confer homophilicity to antibodies as a covalent conjugate. Homophilized antibodies have enhanced potency in target binding, induction of apoptosis, complement fixation and receptor-mediated signal growth inhibition. Titration of homophilic antibodies reveals a dose response skewed toward lower concentrations. The immunotherapeutic utility of homophilized antibodies has been demonstrated in vitro and in animal models. Clinical studies are needed to establish homophilic antibodies as novel, potent, immunotherapeutic agents.