Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond the endogenous formation of advanced glycation endproducts (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production, and consumption of highly processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signalling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.