Atopic dermatitis (AD) lesions are characterized by differences in the activation state of endothelial cells and vascular smooth muscle cells and the release of inflammatory mediators by and toward the vasculature. The vascular system, including endothelial cells and smooth muscle cells, is ultimately involved in clinical symptoms of AD, such as erythema, edema, leukocyte recruitment, and white dermographism. Various mediators and bidirectional neurovascular interactions regulate the inflammatory response during AD. T cell–endothelial cell interactions are a crucial component to establish acute AD. Various immune cells, including monocytes and mast cells, communicate with the endothelium by releasing inflammatory mediators, thereby stimulating inflammatory mediator release from activated endothelial cells. The process of adhesion, tethering, and transmigration of infiltrating cells is a highly regulated and an active communication process between endothelial cells and leukocytes. Endothelial cells play a pivotal role in the pathophysiology of AD and represent future targets for the treatment of AD.