Current therapies to manage obesity are based on energy restriction and physical activity promotion. However, the role of specific dietary components for long-term weight maintenance is under debate. This review aims to illustrate some lessons from the pan-european diogenes study, a randomized, controlled dietary intervention study, which investigated the role of dietary protein and glycemic index (gi) on weight maintenance in overweight/obese european families. For 6 months, families were randomly assigned to five ad libitum weight-maintenance diets: low-protein (lp)/low-gi (lgi), lp/high-gi (hgi), high-protein (hp)/lgi, hp/hgi, and a control diet. The main result was that the hp/lgi diet was more successful for maintaining weight loss, and has beneficial effects on cardiometabolic risks. Outcomes regarding gender, age, the model of delivery, genetic factors, and benefits on insulin sensitivity, cardiovascular risk, bone turnover, and inflammation are also reported.