The major impediment to the development of murine monoclonal antibodies (mAbs) for therapy in humans has been the difficulty in reducing their potential immunogenicity. XenoMouse¿trade mark omitted¿ mice obviate this problem while retaining the relative ease of generating mAbs from a mouse. XenoMouse strains include germline-configured, megabase-sized YACs carrying portions of the human IgH and Igkappa loci, including the majority of the variable region repertoire, the genes for Cmicro, Cdelta and either Cgamma1, Cgamma2, or Cgamma4, as well as the cis elements required for their function. The IgH and Igkappa transgenes were bred onto a genetic background deficient in production of murine immunoglobulin. The large and complex human variable region repertoire encoded on the Ig transgenes in XenoMouse strains support the development of large peripheral B cell compartments and the generation of a diverse primary immune repertoire similar to that from adult humans. Immunization of XenoMouse mice with human antigens routinely results in a robust secondary immune response, which can ultimately be captured as a large panel of antigen-specific fully human IgGkappa mAbs of sub-nanomolar affinities. Monoclonal antibodies from XenoMouse animals have been shown to have therapeutic potential both in vitro and in vivo, and appear to have the pharmacokinetics of normal human antibodies based on human clinical trials. The utility of XenoMouse strains for the generation of large panels of high-affinity, fully human mAbs can be made available to researchers in the academic and private sectors, and should accelerate the development and application of mAbs as therapeutics for human disease.