Advances in therapeutics have dramatically improved short-term graft survival, but the incidence of chronic rejection has not changed in the past 20 years. New insights into mechanism are sorely needed at this time and it is hoped that the development of predictive biomarkers will pave the way for the emergence of preventative therapeutics. In this review, we discuss a paradigm suggesting that sequential changes within graft endothelial cells (EC) lead to an intragraft microenvironment that favors the development of chronic rejection. Key initial events include EC injury, activation and uncontrolled leukocyte-induced angiogenesis. We propose that all of these early changes in the microvasculature lead to abnormal blood flow patterns, local tissue hypoxia, and an associated overexpression of HIF-1alpha-inducible genes, including vascular endothelial growth factor. We also discuss how cell intrinsic regulators of mTOR-mediated signaling within EC are of critical importance in microvascular stability and may thus have a role in the inhibition of chronic rejection. Finally, we discuss recent findings indicating that miRNAs may regulate EC stability, and we review their potential as novel non-invasive biomarkers of allograft rejection. Overall, this review provides insights into molecular events, genes, and signals that promote chronic rejection and their potential as biomarkers that serve to support the future development of interruption therapeutics.