To introduce temporal control in genetic experiments targeting the endothelium, we established a mouse line expressing tamoxifen‐inducible Cre‐recombinase (Cre‐ER^T2) under the regulation of the vascular endothelial cadherin promoter (VECad). Specificity and efficiency of Cre activity was documented by crossing VECad‐Cre‐ER^T2 with the ROSA26R reporter mouse, in which a floxed‐stop cassette has been placed upstream of the β‐galactosidase gene. We found that tamoxifen specifically induced widespread recombination in the endothelium of embryonic, neonatal, and adult tissues. Recombination was also documented in tumor‐associated vascular beds and in postnatal angiogenesis assays. Furthermore, injection of tamoxifen in adult animals resulted in negligible excision (lower than 0.4%) in the hematopoietic lineage. The VECad‐Cre‐ER^T2 mouse is likely to be a valuable tool to study the function of genes involved in vascular development, homeostasis, and in complex processes involving neoangiogenesis, such as tumor growth. Developmental Dynamics 235:3413–3422, 2006. © 2006 Wiley‐Liss, Inc.