The vascular endothelium serves as an indispensable border for the interaction and exchange of molecules and cells between the blood flow and tissues. Upon transplantation, the endothelium of the allograft is the first to come into contact with the recipient’s blood and becomes injured by alloreactive and nonalloreactive stimuli. Repetitive injuries lead to severe damage of the endothelium resulting in the development of chronic rejection over time. The objective of this chapter is to highlight recent insights into the most relevant endothelial molecules, mediators, and pathways crucial in the evolvement of chronic organ rejection. We also discuss new avenues of drugs that can diminish or prevent damage to the endothelium leading to an otherwise irreversible development of chronic organ rejection.