In this study, we aim to (1) summarize the current knowledge about the role of obesity in the onset and progression of CVD, (2) discuss the role of the AGE–RAGE system as a pathway promoting obesity and linking obesity to CVD, and (3) highlight available strategies for reducing AGE–RAGE system activation and the associated beneficial effects. This evidence concerns the gene AGER and obesity due to melanocortin 4 receptor deficiency.