Therapeutic monoclonal antibodies have shown limited efficacy and safety owing to immunogenicity of mouse sequences in humans. Among the approaches developed to overcome these hurdles were transgenic mice genetically engineered with a 'humanized' humoral immune system. One such transgenic system, the XenoMouse, has succeeded in recapitulating the human antibody response in mice, by introducing nearly the entire human immunoglobulin loci into the germ line of mice with inactivated mouse antibody machinery. XenoMouse strains have been used to generate numerous high-affinity, fully human antibodies to targets in multiple disease indications, many of which are progressing in clinical development. However, validation of the technology has awaited the recent regulatory approval of panitumumab (Vectibix), a fully human antibody directed against epidermal growth factor receptor (EGFR), as treatment for people with advanced colorectal cancer. The successful development of panitumumab represents a milestone for mice engineered with a human humoral immune system and their future applications.