Review the role of coronary artery calcium (CAC) testing in designing future clinical trials in primary prevention. While there are numerous new agents that have been found to lower cardiovascular event rates in clinical trials, these studies have required a large sample size, in part due to low event rates as well as improved baseline treatments. More precise risk assessment could allow for better identification of individuals who stand to derive the most benefit from various therapies. Coronary CAC testing offers a simple method for identifying high-risk primary prevention cohorts, and thus may allow for improved efficiency of clinical trials, enhanced efficacy of various therapies, and ultimately more favorable cost-effectiveness estimates. The use of CAC testing as part of the inclusion criteria used in clinical trials may result in identifying high-risk individuals who were previously not included in such studies while achieving favorable absolute risk reductions. The advantages afforded by using CAC to enrich clinical trials offer a potential road map for future clinical trials in primary prevention.