The ability to produce a diverse repertoire of fully human monoclonal antibodies may have significant applications to human therapy. One of the most promising approaches to the production of therapeutic human monoclonal antibodies is the creation of a mouse strain engineered to produce a large repertoire of human antibodies in the absence of mouse antibodies. Recently, such mice have been generated by introducing segments of human immunoglobulin loci into the germlines of mice deficient in mouse antibody production as a result of gene targeting. These mice produce significant levels of fully human antibodies with a diverse adult-like repertoire and, upon immunization with antigens, generate antigen-specific fully human monoclonal antibodies. Such strains of mice may provide the optimal source for producing human monoclonal antibodies with high affinity and specificity against a broad spectrum of antigens, including human antigens.