Interactions between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are fundamental in maintaining vascular integrity, structure and function. ECs and VSMCs act as a coupled system for transmission of signals from the endothelium to the underlying vascular media and vice versa. Such interactions are fundamental in the regulation of vascular integrity, structure and function. Communications between ECs and VSMCs occur through synthesis and release of mediators or through direct cell-to-cell contact. ECs regulate vascular tone through vasorelaxing molecules such as nitric oxide (NO), hydroxyeicosatetraenoic acid (HETE), and prostacyclin (PGI) and vasoconstricting molecules such as endothelin-1 and thromboxane. Recent studies demonstrate that ECs regulate VSMC proliferation, migration, differentiation, and gene expression through reactive oxygen species (ROS). All vascular cell types, including ECs, VSMCs, and adventitial fibroblasts produce superoxide hydrogen peroxide (H2O2), and NO, primarily through NADPH oxidases (Noxa,2,4,5). Physiologically ROS are produced in a controlled manner at low concentrations and function as inter- and intracellular signaling molecules. In pathological conditions increased activity/expression of ROS generating enzymes or decreased defenses by antioxidants in the vasculature result in increased bioavalability of ROS, leading to oxidative stress and vascular damage. In basal conditions ECs protect VSMCs from oxidative injury, in part through upregulation of VSMC antioxidant systems, whereas in pro-inflammatory conditions this effect is blunted, resulting in oxidative stress and vascular injury. VSMC-derived superoxide has been implicated in the quenching of NO in ECs to form injurious ONOO-, which further promotes vascular inflammation and injury. Emerging evidence indicates that cross talk between oxidant systems occurs at multiple levels within the vessel wall. Not only can ROS produced within ECs influence ROS formation in VSMCs, and vice and versa, but ROS produced by one cell type can influence signaling in adjacent cells. This presentation focuses on the role of ROS in the cross-talk between ECs and SMCs and the molecular processes that modulate vascular function and structure.