Advanced glycation end products (AGEs), S100/calgranulins, and HMGB1 proteins supposedly play a pivotal role in diabetes mellitus and other chronic inflammatory diseases by promoting cellular dysfunction via binding to cellular surface receptors. Particularly, engagement of the receptor for AGEs (RAGE) has gained major attention because it converts short-lasting cellular activation in sustained cellular dysfunction. Consistently, blockade of ligand-RAGE interaction with soluble RAGE (sRAGE) suppresses chronic cellular activation and dysfunction in animal models of chronic diseases. RAGE-/- mice, however, demonstrate that the protection conferred by RAGE deficiency is lower than that mediated by sRAGE. Furthermore, RAGE-/- mice can be protected by sRAGE in certain settings of the adaptive immune response. This finding implies that abounding RAGE ligands overworking the RAGE pathway might also activate other receptors.