Human antibody repertoires can be created in transgenic mice following the introduction of human immunoglobulin heavy and light chain genes in their germline configuration. Transgene constructs or transloci have been obtained by plasmid assembly, cloning in yeast artificial chromosomes, and the use of chromosome fragments. Translocus integration and maintenance in transgenic mouse strains has been achieved by pronuclear DNA injection into oocytes and various transfection methods using embryonic stem cells. The human DNA segments rearrange faithfully in the mouse and produce extensive V(D)J combinations. Specific human monoclonal antibodies of high affinity for use in therapeutic applications have been produced from these translocus mice.