The integrity of blood vessels is critical to vascular homeostasis. Maintenance of vascular integrity has been conventionally regarded as a passive process that is largely dependent on continuous blood flow. Recent studies, however, have begun unveiling molecular processes essential for maintenance of vascular integrity and homeostasis under physiological conditions, leading to the notion that maintenance of the vasculature is an active biological process that requires continuous, basal cellular signaling. Failure of this system results in serious consequences such as hemorrhage, edema, inflammation, and tissue ischemia. In this review, we will discuss the emerging concepts in regulation of vascular integrity with the emphasis on structural components of blood vessels that are essential for vascular maintenance.