Reducing sugars can react non-enzymatically with the amino groups of proteins, lipids, and nucleic acids to initiate a complex series of rearrangements and dehydrations, and then to produce a class of irreversibly cross-linked heterogeneous fluorescent moieties, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs in numerous tissues have been known to progress in a normal aging process and at an accelerated rate under hyperglycemic and/or oxidative stress conditions. There is a growing body of evidence that interaction of AGEs with a cell-surface receptor termed receptor for AGEs (RAGE) elicits oxidative stress generation and subsequently evokes proliferative, angiogenic, and inflammatory reactions, thereby being involved in the development and progression of various types of cancers. These observations suggest that accumulation of AGEs and resultant activation of the RAGE signaling pathway could partly explain the increased risk of a variety of cancers in patients with diabetes or in elderly subjects. This article summarizes the pathological role of RAGE activation by AGEs and other ligands in tumor growth and metastasis and its therapeutic interventions for the life-threatening disorders.