Cardiovascular disease remains the leading cause of death in both men and women in the United States. Treating elevated low-density lipoprotein (LDL) cholesterol has been shown to be very effective in reducing the rate of coronary heart disease (CHD) in primary prevention trials; however, the data are not as robust for treating individuals categorized at either lower risk for CHD or with below-average LDL cholesterol levels. The next frontier for investigation will include strategies to determine who in these lower risk categories should be treated with statins. The growing epidemics of obesity, diabetes, and metabolic syndrome also loom as major problems that need to be incorporated into any strategy that focuses on the prevention of cardiovascular disease. In individuals with multiple cardiovascular risk factors, combination therapies tailored to address each individual’s risk profile need to be considered to best decrease the likelihood of their first coronary event.