The receptor for advanced glycation end-products (RAGE) and its ligands are intimately involved in the pathobiology of a wide range of diseases that share common features, such as enhanced oxidative stress, immune/inflammatory responses, and altered cell functions. Soluble forms of RAGE (sRAGE), including the splice variant endogenous secretory (es)RAGE, have been found circulating in plasma and tissues. Experimental data suggest that these isoforms may neutralize the ligand-mediated damage by acting as a decoy. Moreover, evidence is mounting to support a role for both sRAGE and esRAGE as biomarkers or endogenous protection factors against RAGE-mediated pathogenesis. In this review, we will focus on clinical and therapeutical implications arising from studies investigating the significance of soluble RAGE isoforms in several clinical settings, including cardiovascular disease, diabetes mellitus, hypercholesterolemia, chronic renal failure, immune/inflammatory diseases, pulmonary diseases, neurodegeneration, and cancer.