Macronutrients are those nutrients (protein, fat, and carbohydrate) that provide energy. The purpose of this review is to highlight findings of three large-scale, isocaloric feeding studies: the Dietary Approaches to Stop Hypertension (DASH) trial, the DASH-Sodium trial, and the Optimal Macro-Nutrient Intake to Prevent Heart Disease (OmniHeart) trial. Each of these trials tested the effects of diets with different macronutrient profiles on traditional cardiovascular disease (CVD) risk factors (ie, blood pressure and blood lipids) in the setting of stable weight. The DASH and DASH-sodium trials demonstrated that a carbohydrate-rich diet that emphasizes fruits, vegetables, and low-fat dairy products and that is reduced in saturated fat, total fat, and cholesterol substantially lowered blood pressure and low-density lipoprotein cholesterol. OmniHeart demonstrated that partial replacement of carbohydrate with either protein (about half from plant sources) or with unsaturated fat (mostly monounsaturated fat) can further reduce blood pressure, low-density lipoprotein cholesterol, and coronary heart disease risk. Results from these trials highlight the importance of macronutrients as a determinant of CVD risk. Furthermore, these results also document substantial flexibility that should enhance the ability of individuals to consume a heart-healthy diet.