The importance of the vascular adventitia is increasingly being recognized not only in vascular disease but also in normal maintenance and homeostasis of vessels. Activation of the adventitia and its resident fibrocytic cells in response to injury, stretch, cytokines, and hormones has been shown to stimulate differentiation, collagen deposition, migration, and proliferation. Importantly, the effects of adventitial fibroblasts are increasingly being ascribed to reactive oxygen species (ROS) produced by adventitial fibroblast NAD(P)H oxidases. Much historical and recent evidence suggests that fibroblast NAD(P)H oxidase) is a harbinger and initiator of vascular disease and remodeling. Data from our laboratory indicate that adventitial fibroblast NAD(P)H oxidase plays a direct and/or paracrine role in neointimal hyperplasia as well as a paracrine role in medial smooth muscle hypertrophy in vivo. We propose that adventitial NAD(P)H oxidase-derived cell-permeant hydrogen peroxide or a byproduct of its oxidation of lipids activates signaling mechanisms in medial smooth muscle leading to the growth response. This review will address the potential role of this adventitial ROS in vascular inflammation and cytokine release to potentiate smooth muscle hypertrophy. We will also survey other signaling pathways involving adventitial NAD(P)H oxidase ultimately leading to changes in vascular phenotype.