Cardiovascular disease remains the leading cause of mortality in the industrialized world. Despite advances in pharmacotherapy and catheter based interventions, coronary artery bypass grafting remains an essential therapeutic modality. The majority of coronary artery bypass operations, as well as other cardiac surgical procedures require the use of ischemic cardioplegic arrest and cardiopulmonary bypass, both of which result in iatrogenic injury to the vasculature and microcirculation. This injury can manifest as impaired vasorelaxation or vasoconstriction, depending upon the organ system involved, resulting in impaired tissue perfusion and the development of edema. Key to this dysfunction are changes in the following: nitric oxide signaling secondary to changes in eNOS and iNOS expression and activity, cyclooxygenase function with increases in pro-inflammatory COX-2 activity, alterations in Protein Kinase C and Mitogen Activated Protein Kinase signaling, and an increase in Vascular Endothelial Growth Factor expression increasing vascular permeability and dilatation. This review discusses our current understanding of cardioplegia and cardiopulmonary bypass induced changes in the vasculature, and therapeutic interventions aimed at modulating the altered signaling pathways.