Preclinical models of human disease, first in vivo then in vitro, have been the source of immense progress in medical research. As researchers have come to understand the genetic heterogeneity of human disease however, we have developed a better understanding of their shortcomings, including a too-often failure to predict the efficacy of biotherapeutics in man. Humanized mice introduce a new era in medical research, but with patho-physiological relevance. (#27999)