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.