Antibodies have been used successfully as therapeutics for over 100 years. The successful development of therapeutic human(ized) monoclonal antibodies (mAbs) in the last 20 years has demonstrated the potency of mAbs but also revealed some of their limitations. Studies in animals and humans demonstrated that it is possible to overcome some of these limitations using mixtures of mAbs or polyclonal antibody (pAb) preparations. pAbs from human and animal plasma are efficacious and safe therapeutics for the treatment of many diseases. Novel technologies are being developed for the production of human pAbs in genetically engineered animals. Immunization of such animals should allow the production of effective and safe high-titer antibody preparations for the treatment of infectious diseases, cancer, and autoimmunity.