In spite of optimal organ preservation techniques, the heart and the lungs remain extremely vulnerable to the ischemia and reperfusion which accompany the transplantation procedure. Following a period of prolonged preservation, the altered phenotype of the graft vasculature results in vasoconstriction, neutrophil sequestration, edema, and thrombosis in the reperfused graft. These parameters of vascular dysfunction translate into primary graft failure and recipient demise. Using endothelial cells exposed to hypoxia and reoxygenation as a simple paradigm for the vascular milieu during organ preservation/transplantation, we have found that second messenger pathways (cAMP and NO/cGMP) are suppressed, neutrophil-endothelial interactions are enhanced, and prothrombotic mechanisms are activated. Using heterotopic rat heart and orthotopic rat lung transplant models, we have shown that supplemention of second messenger pathways or interference with neutrophil-endothelial interactions can significantly enhance preservation. Understanding mechanisms of vascular dysfunction within the graft should help define clinically relevant therapeutic targets to enhance heart or lung preservation for transplantation.