Cholesterol crystals have long been recognized as part of atherosclerotic plaques. They have been visualized by light microscopy as empty spaces or imprints where crystals were once present and then dissolved by tissue processing. Thus, until now, their role in atherosclerosis and plaque rupture had been considered to be inert. However, by the processing of tissue without ethanol it was possible to visualize their extensiveness and potential role in tissue injury. Also, it was demonstrated that cholesterol expands in volume when crystallizing from the liquid to the solid state, which is the presumed cause of plaque rupture by sharp-tipped crystals growing out of the plaque’s necrotic core. Specifically, in patients who died of myocardial infarction, all culprit coronary lesions had extensive cholesterol crystals perforating the fibrous cap and intima, while those patients who died of other causes and had plaques did not have crystals perforating the cap and intima. Additionally, cholesterol crystals traveling downstream from the plaque rupture site can scrape the endothelium and promote vasospasm. Moreover, cholesterol crystals lodging into the muscle can trigger an inflammation with necrosis independent of circulatory compromise or ischemia. These findings suggest that cholesterol crystals could play a critical role in plaque rupture, as well as vascular and myocardial injury.