There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) system are implicated in various disorders, including vascular complications in diabetes, cardiovascular disease, neurodegenerative diseases, inflammatory and autoimmune disorders, and cancer growth and metastasis. Indeed, the engagement of RAGE with AGEs elicits oxidative stress generation and evokes inflammatory and thrombogenic responses, thus playing an important role in these devastating disorders. Moreover, since administration of a recombinant soluble form of RAGE (sRAGE), has been shown to block the AGE-RAGE signaling pathway in animal models, exogenously administered sRAGE may capture and eliminate circulating AGEs, thus protecting against the AGE-elicited tissue damage by acting as a decoy receptor for AGEs. Recently, sRAGE has been identified in humans. However, there are a few comprehensive papers about the regulation and role of sRAGE in humans. Therefore, in this paper, we review the kinetics, regulation and pathophysiological role of sRAGE in humans. We further discuss the potential clinical utility of measuring sRAGE in various disorders as a biomarker.