Adventitia surrounds, nourish, and protect large conductance vessels. This important outer layer has long been forgotten by researchers because interest in vascular diseases has focused mainly on resistance arteries, as shown by the numerous publications on the subject. However, involvement of large vessels in the pathogenesis of vascular diseases is beginning to be recognized. Indeed, the stiffness of conductance arteries could be a precursor event of high blood pressure. Pathological changes that occur in adventitia, increased vasa vasorum permeability for example, may lead or precipitate vascular diseases. Adventitia can also be affected by luminal events like shear stress and possibly atherosclerosis that may trigger adverse responses in the adventitial tissue. These adventitial changes and interrelationships, as well as the structure, including the afferent and efferent autonomic nervous system, and functions of adventitia are the subject of the present review. There is no doubt that the medical and scientific community would greatly benefit from awareness and a better consideration of adventitia and that more studies focusing on this part of blood vessels will lead to an improved comprehension of the different diseases affecting them.