Reactive oxygen species (ROS) have been implicated in tissue remodeling in a variety of cardiovascular diseases including hypertension, stroke, myocardial infarction, congestive heart failure and renal microvascular disease. Undoubtedly, the mechanisms involved are complex; however there is now compelling evidence that an increase in ROS during hypertension plays a pivotal role in this process. Studies suggest that in hypertension and other vascular disease, there is an imbalance in oxidant-generating vs. oxidant-catalyzing systems, leading to a build-up of endogenous superoxide anion (O₂^–) and hydrogen peroxide (H₂O₂). We and others have shown that the adventitia is a major site of vascular ROS production and have proposed that adventitial fibroblast NAD(P)H oxidase-derived ROS is the sensor and messenger for the early development of systemic vascular disease. This presentation will focus on the paracrine contribution of adventitial fibroblasts, their NAD(P)H oxidase(s) and the role of attendant ROS in neointimal growth and medial hypertrophy in systemic arteries. Until recently the contribution of the adventitia to vascular function has largely been ignored except for reference to its role in the structural support for the blood vessel and as a scaffold for sympathetic nerve endings and the vasa vasorum. As such, the adventitia has been viewed with much the same skepticism as once was reserved for the endothelium, largely being considered an inert physical barrier separating the medial smooth muscle from other tissues. This “outsider” status of the adventitia is clearly giving way to a rapidly growing interest in this relatively new frontier in vascular biology. Multiple findings support a seminal and complex role for adventitial ROS in the recruitment of inflammatory cells, production of extracellular matrix and general remodeling of the vessel wall in cardiovascular disease.