Whether endothelium-derived relaxing factor (EDRF) is important in the physiology and pathology of vascular reactivity must await the discovery of the nature of the factor and an appropriate antagonist substance. Nevertheless the demonstration that EDRF is powerful, short-lived and can be released by a wide variety of stimuli adds a new dimension to our knowledge of the control of the circulation. The macroenvironment of the vessel wall is influenced by nerves, blood-borne factors and the architecture of the wall. The discovery of a role of the endothelial cell has for the first time forced pharmacologists to consider cell-cell interactions in the micro-environment of the blood-vessel wall. This is a potentially important target for new therapy.