The use of medical therapies that target established atherosclerotic risk factors has had a profound impact on the incidence of cardiovascular events. However, the majority of clinical events are not prevented. This highlights the need to identify new therapeutic targets to achieve further clinical benefit. A number of pathological events within the arterial wall, which contribute to atheroma formation, represent potential targets for therapeutic intervention. The use of surrogate markers of clinical efficacy has become increasingly popular in the assessment of novel therapies. Imaging of atherosclerotic plaques and their progression by intravascular ultrasound has been used in a number of studies to evaluate therapeutic strategies. Using this analytical approach, in the recently reported acyl cholesteryly acyl transferase intravascular atherosclerosis treatment evaluation (ACTIVATE) study, the experimental acyl-coenzyme:cholesterol acyltransferase inhibitor, pactimibe, was reported to have a detrimental impact on plaque progression. This article will highlight the potential role for use of imaging modalities in the assessment of agents designed to prevent atherosclerotic cardiovascular disease.