A number of recent epidemiologic observations support the need for new and broader strategies to reduce serum cholesterol levels on a populationwide basis. First, the limited data available suggest a halt in the declining incidence of coronary artery disease (CAD) in the United States since 1990, raising concerns about our current strategies to promote primary prevention of CAD. Data from the 1970s and 1980s support a key role for population-wide cholesterol lowering as a strategy to reduce CAD. Second, large and carefully performed surveys support no further reductions in serum cholesterol levels in the US population since 1990. Is this observation and that of stagnating declines of CAD incidence a coincidence? Interestingly, the lack of cholesterol level reduction occurred in the setting of increased use of prescription cholesterol-lowering drugs, suggesting that drug treatment of the highest-risk persons alone will not shift the population curve. Third, the treatment gap persists, with recent populationwide data suggesting that half of all people with hypercholesterolemia (≥200 mg/dL) are unaware of their condition, only half of those persons aware are treated, and only half of those treated are controlled. Finally, the moderate-risk population (10% to 20% risk of CAD over 10 years) is sizable in the ages recommended for over-the-counter statin use (≥45 years in men, ≥55 years in women). Risk reduction in this group, which contributes a significant portion of CAD cases, should be part of any program to reduce the population burden of CAD.