Acute coronary syndrome (ACS) is often associated with the rupture of vulnerable atherosclerotic plaque, coronary thrombus formation, and abrupt limitation of blood flow, leading to adverse outcomes. Passivation of vulnerable plaque represents a therapeutic concept that has the potential to prevent or limit the magnitude of a new rupture in order to reduce the recurrence or severity of events. Plaque passivation can be defined as a process by which the structure or content of the atherosclerotic plaque is changed to reduce the risk of subsequent rupture and thrombosis. This may be achieved by using strategies that address different components of the plaque or the endothelium. The following factors can affect the susceptibility of plaque to rupture: macrophage infiltration; accumulation of inflammatory cells; paracrine secretion of enzymes that may cause degradation of the fibrous cap of coronary plaque; shear stress; circadian rhythm variation in stress hormone release; and infectious agents. The use of pharmacologic agents to reduce plaque vulnerability by passivation has been explored. Clinical studies demonstrate that lipid-modifying agents (e.g., statins), antiplatelet agents (acetylsalicylic acid, thienopyridines, thianopyridines, glycoprotein IIb/IIIa inhibitors), and antithrombotic agents (unfractionated heparin and low-molecular-weight heparin) can reduce the occurrence of acute coronary events in ACS patients. In addition, angiographic studies suggest that statins may also promote regression of atherosclerosis. Angiotensin-converting enzyme inhibitors, niacin, and calcium antagonists may also contribute to plaque passivation. This article reviews atherosclerotic plaque development and vulnerability and discusses some clinical studies highlighting the role of plaque passivation in the management of ACS patients.