Cardiovascular disease remains the leading cause of death in the United States despite a 50% decrease in deaths from myocardial infarction and stroke in the past 30 years associated with improvements in blood pressure and lipid control. The National Health and Nutrition Evaluation Survey found that the least prevalent metrics of cardiovascular health in adults were healthy diets, normal weights, and optimal levels of exercise. A further reduction in rates of cardiovascular disease will require an increase in exercise. Clinicians who encourage exercise in middle-aged patients face several dilemmas. This article reviews exercise-related risks for sudden death and the performance of a global cardiovascular risk assessment. The need for additional preexercise risk stratification with electrocardiogram, graded exercise testing, or echocardiography is outlined. In addition, the optimum choice of medications for hypertension or dyslipidemia treatment and the effects of these medications and aspirin on endurance exercise are reviewed.