Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the ad-vances in cardiology, there are yet many unanswered questions about the natural history of cor-onary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, “vulnerable” plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovas-cular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as en-dothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical per-spectives of these findings.