Intravascular ultrasound has emerged as the preferred imaging modality for the characterization of atherosclerotic plaque within the coronary arteries. Ultrasonic imaging reveals the presence of more extensive atheroma than suggested by conventional angiography in patients with coronary artery disease. The ability to precisely quantify atheroma volume in an arterial segment at different time points provides the unique opportunity to investigate the factors that influence the natural history of atheroma progression. Accordingly, serial intravascular ultrasound has been incorporated into a number of clinical trials that have evaluated the impact of medical therapies that modify established risk factors and novel pathological targets. This article will review the increasing role of imaging modalities in the assessment of atherosclerosis and factors that influence its natural history.