Drug-induced vascular injury (DIVI) is a serious problem in preclinical studies of vasoactive molecules and for survivors of pediatric cancers. DIVI is often observed in rodents and some larger animals, primarily with drugs affecting vascular tone, but not in humans; however, DIVI observed in animal studies often precludes a drug candidate from continuing along the development pipeline. Thus, there is great interest by the pharmaceutical industry to identify quantifiable human biomarkers of DIVI. Small-scale endothelialized tissue-engineered blood vessels using human cells represent a promising approach to screen drug candidates and develop alternatives to cancer therapeutics in vitro. We identify several technical challenges that remain to be addressed, including high-throughput systems to screen large numbers of candidates, identification of suitable cell sources and establishing and maintaining a differentiated state of the vessel wall cells. Adequately addressing these challenges should yield novel platforms to screen drugs and develop new therapeutics to treat cardiovascular disease.