The receptor for advanced glycation endproducts (RAGE) interacts with a unique repertoire of ligands that form and collect in the tissues and circulation in diabetes mellitus, aging, inflammation, renal failure, and obesity. RAGE is expressed on multiple cell types linked to tissue perturbation in these settings. This brief review focuses on the role of RAGE in monocytes/macrophages and how RAGE ligand engagement on these cells mediates seminal changes in monocyte/macrophage migration, oxidative stress, cholesterol efflux, and pro- versus anti-inflammatory cues that signal to tissue damage. Studies using mice devoid of Ager (gene encoding RAGE) or pharmacological antagonists of RAGE are protective in animal models of diabetes mellitus, atherosclerosis, and high-fat diet–induced obesity, in least in part through key roles in monocytes/macrophages. RAGE signal transduction requires the interaction of RAGE cytoplasmic domain with the formin, DIAPH1 (diaphanous 1) and novel antagonists of this interaction show significant promise in attenuation of the maladaptive effects of RAGE ligands in cellular and in vivo models. Finally, this brief review discusses evidence for RAGE axis perturbation in human monocytes/macrophages and how tracing RAGE activity in these cells may identify target engagement biomarkers of RAGE antagonism for future clinical trials.