Widespread popularity of high-protein diets has drawn controversy as well as scientific interest. By reducing intake of carbohydrates and increasing consumption of fats and proteins, such diets are thought to increase satiety, facilitate weight loss, and improve cardiovascular risk factors. In recent years, many randomized controlled studies have compared the effects of higher-protein diets on weight loss and cardiovascular risk factors with those of lower-protein diets. The aim of this review was to provide an overview of experimental and epidemiologic evidence regarding the role of protein in weight loss and cardiovascular risk. Emerging evidence from clinical trials indicates that higher-protein diets increase short-term weight loss and improve blood lipids, but long-term data are lacking. Findings from epidemiologic studies show a significant relationship between increased protein intake and lower risk of hypertension and coronary heart disease. However, different sources of protein appear to have different effects on cardiovascular disease. Although optimal amounts and sources of protein cannot be determined at this time, evidence suggests a potential benefit of partially replace refined carbohydrates with protein sources low in saturated fats.