The interaction between the vulnerable atherosclerotic plaque prone to disruption and thrombus formation is the cornerstone of acute coronary syndrome (ACS). Although distinct from one another, the atherosclerotic and thrombotic processes appear to be interdependent, hence the term atherothrombosis. Inflammation is a crucial common pathophysiological mechanism. Overall, the association of plaque vulnerability and ACS has been well documented. Given the multifactorial origin of atherothrombosis the best preventive approach should be aggressive management of all the risk factors. New interventions should be directed toward decreasing vulnerability of the lesions thereby decreasing the risk of ACS.