Coronary artery disease (CAD) is highly heritable, and genetically determined risk factors have long been known to play a significant role in the development and clinical manifestations of the disease. The technological advances over the past decade have enabled faster and more comprehensive genetic analyses including large genome-wide association studies (GWAS), which have revealed a plethora of genetic variants that affect the risk of CAD. Individually, these genetic variants have small effects; however, when combined into polygenic risk scores (PRSs), their total effect is large. Numerous PRSs have been developed and validated, consistently finding an increased risk for CAD in the extreme percentiles relative to the rest of the population. These observations have raised expectations for the clinical utility of PRSs, for example as a guide to early intervention and primary prevention in individuals at high risk.1 However, whether PRSs improve risk prediction when added to current guideline-based algorithms has been debated.2,3 Combined with the clinical, political, and not least commercial focus on the application of personalized medicine, there has been a significant emphasis on implementing PRSs into routine clinical practice. Nevertheless, the successful integration of PRSs into clinical practice has been limited by several major challenges. First, it must be shown convincingly that the PRS provides meaningful risk reclassification in the population of interest. Additionally, studies need to evaluate whether addition of PRSs to clinical risk factors will improve clinical outcomes in the population, and thereby change from pure risk prediction towards clinical relevance.4 Second, the application, interpretation, limitations, and communication of the PRS results are major and underappreciated challenges. The treating clinician should understand the methods and assumptions that underlie the PRS, enabling him or her to communicate this information to the patient. The PRS report must therefore convey enough information to be clinically meaningful yet be simple enough to allow for interpretation in a fast-paced clinical setting with limited time available for each patient.5 Third, any adoption of changes to current clinical practices depends on the perception of usefulness, expected effort, trust in the outcome, and ease of use, in addition to the above-mentioned knowledge required by the treating clinician.6 There are currently no clinical guidelines recommending the use of PRSs, and consequently no guidance is available addressing these challenges. Importantly, while current guidelines for primary prevention of cardiovascular disease rely on established risk factors to provide estimates of absolute clinical risk within 5–10 years,7–9 PRSs report relative genetic risk in relation to the average of a given population. At present, there is no recommended strategy to combine these risk estimates.