Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in the United States and worldwide. A link between diet and CVD is well established, with dietary modification a foundational component of CVD prevention and management. With the discovery of bioactive components beyond the essential nutrients of foods, a new era of nutritional, medical, botanical, physiologic, and analytical sciences has unfolded. The ability to identify, isolate, purify, and deliver single components has expanded the dietary supplement business and health opportunity for consumers. Lycopene is an example of a food component that has attracted attention from scientists as well as food, agriculture, and dietary supplement industries. A major question, however, is whether delivering lycopene through a supplement source is as effective as or more effective than consuming lycopene through whole food sources, specifically the tomato, which is the richest source of lycopene in the Western diet. In this review, we examined clinical trials comparing the efficacy of lycopene supplements with tomato products on intermediate CVD risk factors including oxidative stress, inflammation, endothelial function, blood pressure, and lipid metabolism. Overall, the present review highlights the need for more targeted research; however, at present, the available clinical research supports consuming tomato-based foods as a first-line approach to cardiovascular health. With the exception of blood pressure management where lycopene supplementation was favored, tomato intake provided more favorable results on cardiovascular risk endpoints than did lycopene supplementation. Indeed, future research that is well designed, clinically focused, mechanistically revealing, and relevant to human intake will undoubtedly add to the growing body of knowledge unveiling the promise of tomatoes and/or lycopene supplementation as an integral component of a heart-healthy diet.