With the rising global incidence and burden of atherosclerotic disease, there is a need to identify new molecular targets that may not only serve as biomarkers of clinical risk, but also therapeutic targets. The efficiency of drug-development processes needs to improve in order to allocate finite resources towards the evaluation of the most promising compounds. Atherosclerosis imaging provides key information regarding mechanistic efficacy of novel compounds, as an intermediary endpoint, prior to the consideration of embarking upon a large-scale, multi-center randomized placebo-controlled trial. Coronary intravascular ultrasonography and B-mode sonography of carotid intima-media thickness will continue to play an important role in evaluating the efficacy of novel anti-atherosclerotic compounds. Functional, molecular imaging of atherosclerotic plaque is emerging as an exciting experimental tool, allowing for an even greater understanding of processes that drive the progression and instability of atherosclerotic disease. However, given the complexity and heterogeneity of biological systems, a global, non-targeted, systems biological approach to biomarker discovery is likely to yield the discovery of novel molecular footprints of disease. As such, metabolomic and lipidomic approaches will elucidate metabolite signatures of interest for biomarker evaluation, for clinical risk prediction, as well as safety and toxicity of experimental treatment compounds. Imaging studies will remain important for evaluating novel therapeutic strategies gleaned from omics-based discoveries, as well acting as a triage to further undertake large-scale clinical evaluation of these promising therapeutic strategies. These approaches will provide an opportunity to better understand atherosclerosis, its complications and effective treatments across multiple ethnic populations worldwide.