In the early days of vascular biology research, the adventitia (the outermost layer of a blood vessel) was essentially ignored for its effect on vascular wall biology. It was largely considered to play a structural role in maintenance of vessel tensile strength and as a matrix from which innervating neurons and the vasa vasorum subserved large vessel function. Our seminal research in this area helped bring to light a paracrine signaling role for the adventitia in vascular homeostasis by demonstrating cross-talk between adventitial NADPH oxidase-derived ROS and remote cellular signaling effecting tone and medial hypertrophy and proliferation.