AbstractIn recent years, gene‐targeting studies in mice have elucidated many molecular mechanisms in vascular biology. However, it has been difficult to apply this approach to the study of postnatal animals because mutations affecting the vasculature are often embryonically lethal. We have therefore generated transgenic mice that express a tamoxifen‐inducible form of Cre recombinase (iCreERT2) in vascular endothelial cells using a phage artificial chromosome (PAC) containing the Pdgfb gene (Pdgfb‐iCreER mice). This allows the genetic targeting of the vascular endothelium in postnatal animals. We tested efficiency of tamoxifen‐induced iCre recombinase activity with ROSA26‐lacZ reporter mice and found that in newborn animals recombination could be achieved in most capillary and small vessel endothelial cells in most organs including the central nervous system. In adult animals, recombination activity was also widespread in capillary beds of skeletal muscle, heart, skin, and gut but not in the central nervous system where only a subpopulation of endothelial cells was labeled. We also tested recombination efficiency in a subcutaneous tumor model and found recombination activity in all detectable tumor blood vessels. Thus, Pdgfb‐iCreER mice are a valuable research tool to manipulate endothelial cells in postnatal mice and study tumor angiogenesis. genesis 46:74–80, 2008. © 2008 Wiley‐Liss, Inc.