Atherosclerosis is a chronic condition with acute cardiovascular manifestations. Most commonly, the acute manifestations of atherosclerosis are triggered by a local arterial occlusion with a thrombus overlying a pre-existing atherosclerotic plaque. Despite landmark advances in the prevention and treatment of cardiovascular disease, it remains the leading cause of morbidity and mortality worldwide, accounting in 2005 for 35% of all deaths in the United States and 30% of all deaths globally. A particular challenge to combating the epidemic of cardiovascular disease is the sudden and often unpredictable nature of its acute manifestations. For many patients with atherosclerosis, the first manifestation is an acute myocardial infarction, sudden cardiac death, or a disabling stroke. This has fueled considerable research aimed at refining existing algorithms for risk stratification and developing new methods to identify subjects before the occurrence of a cardiovascular event so that primary preventive measures can be initiated. Furthermore, among patients who have survived a cardiovascular event, the risk of a subsequent event remains relatively high-approaching 1 in 4 despite aggressive treatment. Such recurrence rates highlight the need for novel approaches to secondary prevention of cardiovascular disease and to the treatment of index events. Over the past two decades, the concept of the "vulnerable plaque" has gained attention as a paradigm to improve risk stratification and potentially lead to newer invasive and non-invasive therapeutic options to prevent and treat atherothrombotic cardiovascular disease. The Effective Health Care Program at the Agency for Healthcare Research & Quality requested a technical brief on the diagnosis and treatment of "vulnerable plaques" of coronary and carotid arteries. Our report is based on a set of key questions designed to explore the concept of "vulnerable plaque" and how this concept could affect the use of existing or developing diagnostic and therapeutic technologies. This report also expands on a technical report on vulnerable plaque that we conducted in 2004. The objective of this report is to assess, with a systematic review approach, the volume and type of evidence available on vulnerable plaque. The purpose is to provide a basis for establishing how the research field is evolving and identify topics that may require further research. We created an "evidence map" that describes the tests that have been evaluated, the populations in which they have been evaluated, and the types of studies that have been used. This review is not a detailed technology assessment based on a systematic review of full-text articles. It does not synthesize or evaluate the results of individual clinical studies and does not make clinical recommendations. "Vulnerable plaque" is still an evolving concept and is not an established medical diagnosis. Therefore, any reference to "vulnerable plaque" in this report concerning its natural history, diagnostic methods, and treatments is by necessity inferential. It refers to conditions that might fall under the current concept of vulnerable plaque but not specifically about vulnerable plaque.