Cardiovascular disease (CVD) accounts for almost 50% of all deaths in industrialized nations. As much as 70% of CVD can be prevented or delayed with dietary choices and lifestyle modifications. Western-style diets, sedentary lifestyles, and cigarette smoking are key modifiable CVD risk factors. Although CVD mortality was trending downward for almost 50 years, a resurgence, both nationally and globally, has occurred. A growing epidemic of obesity ("globesity"), decreasing physical activity, and persistent cigarette smoking are major behavioral factors underlying this change. Diet and lifestyle increase CVD risk both directly and indirectly. Direct effects include biological, molecular, and physiologic alterations, including inflammatory stimuli and oxidative stresses. Indirect effects include diabetes, dyslipidemias, and hypertension. However, trials studying links between diet and CVD remain notoriously difficult to execute and interpret. Diet interventions are typically confounded by other aspects of an overall diet as well as by lifestyle. Furthermore, benefits derived from a specific dietary or lifestyle intervention may not be proportional to the degree of risk posed by the unhealthy diet or lifestyle. Nonetheless, therapeutic rationale for diet and lifestyle are supported by basic and clinical research. Key components of a healthy aggregate diet include 1) reduced caloric intake; 2) reduced total fat, saturated fat, trans fat, and cholesterol with proportional increases in monosaturated, n-3 (omega-3), and n-6 fatty acids; 3) increased dietary fiber, fruit, and vegetables; 4) increased micronutrients (eg, folate, B6, B12); 5) increased plant protein in lieu of animal protein; 6) reduced portions of highly processed foods; and 7) adopting a more Mediterranean or "prudent" dietary pattern over the prevailing "western" dietary pattern. Key lifestyle interventions include increased physical activity and smoking cessation. Translation of the benefits of healthy diet and lifestyle to the wider population requires both individual and public health strategies targeting at-risk groups.