Family history assessment can be used to combine population-wide health promotion and risk-reduction efforts with a high-risk, targeted approach to help reduce the burden of cardiovascular disease (CVD). Family history is an independent predictor of CVD, and the upper portion of the family history distribution explains a larger fraction of CVD in the population than can be explained by extreme values of other risk factors (e.g., blood pressure and cholesterol). A positive family history of disease captures the underlying complexities of gene-gene and gene-environment interactions by identifying families with combinations of risk factors, both measured and unmeasured, that lead to disease expression. Family history is a useful tool for identifying most prevalent cases of CVD and for population-wide disease-prevention efforts. A positive family history also identifies the relatively small subset of families in the population at highest risk for CVD who may benefit most from targeted screening and intensive intervention.