Clinical trials assessing the effect of medical therapies on atherosclerotic plaques have hitherto employed invasive imaging techniques such as intravascular ultrasound (IVUS). This has limited the study population to high-risk patients in whom invasive coronary angiography is indicated; moreover, IVUS typically is performed utilizing a target lesion-based analysis. Recently, comprehensive quantitative analysis of all atherosclerotic plaques in the complete coronary artery network has become possible through the use of coronary computed tomography angiography (CCTA). Excellent inter-observer and inter-scan reproducibility of CCTA has been reported. Several studies have already tested the applicability of CCTA-measured plaque volume changes as an imaging surrogate endpoint in clinical trials and have found positive results. Further, substantial evidence supports the use of CCTA as a novel imaging surrogate that can accurately assess the changes in plaque characteristics according to medical treatment. In this review, we summarize current evidences that support the use of CCTA as a novel imaging surrogate that can replace IVUS in evaluating the results of treatment. We also attempt to determine whether the technological advances in CCTA will extend its application beyond use as a diagnostic method in clinical practice to use in large-scale clinical trials.