There is substantial evidence that genetic factors contribute to coronary artery disease (CAD). Currently, family history collection and interpretation is the best method for identifying individuals with genetic susceptibility to CAD. Family history reflects not only genetic susceptibility, but also interactions between genetic, environmental, cultural, and behavioral factors. Stratification of familial risk into different risk categories (e.g., average, moderate, or high) is possible by considering the number of relatives affected with CAD and their degree of relationship, the ages of CAD onset, the occurrence of associated conditions, and the gender of affected relatives. Familial risk stratification should improve standard CAD risk assessment methods and treatment guidelines (e.g., Framingham CAD risk prediction score and Adult Treatment Panel III guidelines). Individuals with an increased familial risk for CAD should be targeted for aggressive risk factor modification. Individuals with a high familial risk might also benefit from early detection strategies and biochemical and DNA-based testing, which can further refine risk for CAD. In addition, individuals with the highest familial risk might have mendelian disorders associated with a large magnitude of risk for premature CAD. In these cases, referral for genetic evaluation should be considered, including pedigree analysis, risk assessment, genetic counseling and education, discussion of available genetic tests, and recommendations for risk-appropriate screening and preventive interventions. Research is needed to assess the feasibility, clinical validity, clinical utility, and ethical, legal, and social issues of an approach that uses familial risk stratification and genetic evaluation to enhance CAD prevention efforts.