Atherosclerosis remains a major cause of morbidity and mortality worldwide, and a thorough understanding of the underlying pathophysiological mechanisms is crucial for the development of new therapeutic strategies. Although atherosclerosis is a systemic inflammatory disease, coronary atherosclerotic plaques are not uniformly distributed in the vascular tree. Experimental and clinical data highlight that biomechanical forces, including wall shear stress (WSS) and plaque structural stress (PSS), have an important role in the natural history of coronary atherosclerosis. Endothelial cell function is heavily influenced by changes in WSS, and longitudinal animal and human studies have shown that coronary regions with low WSS undergo increased plaque growth compared with high WSS regions. Local alterations in WSS might also promote transformation of stable to unstable plaque subtypes. Plaque rupture is determined by the balance between PSS and material strength, with plaque composition having a profound effect on PSS. Prospective clinical studies are required to ascertain whether integrating mechanical parameters with medical imaging can improve our ability to identify patients at highest risk of rapid disease progression or sudden cardiac events.