The endothelium is an uninterrupted, smooth, and nonthrombogenic surface that not only forms a highly selective permeability barrier, but also synthesizes and releases a plethora of vasoactive substances, notably nitric oxide, involved in regulating vascular tone and platelet aggregation. The underlying cause of most forms of cardiovascular disease, notably myocardial infarction and stroke, is atherosclerosis, a process that is initiated by endothelial dysfunction and sustained by intimal thickening, deposition of (low-density) lipoprotein, and invasion by macrophages and other white blood cells. In addition, endothelial activation leads to the expression and release of proinflammatory surface molecules such as tissue factor. Severe coronary stenosis causes angina, while plaque rupture and endothelial erosion release highly procoagulant plaque content into the bloodstream, activating platelets and initiating the coagulation cascade, with thrombus formation and vessel occlusion. Percutaneous coronary intervention, platelet inhibitors, and anticoagulants help to restore patency in acute occlusion, while long-term primary and secondary prevention with statins, angiotensin-convertingenzyme inhibitors, angiotensin-II receptor blockers, and calcium channel blockers enhances endothelial function. This review updates the authors’ previous publications, focusing on blood/vessel wall interaction and its importance for atherothrombosis and its management...