The Receptor for Advanced Glycation End Products (RAGE) and its ligands are expressed in multiple cancer types and are implicated in cancer progression. Our lab has previously reported higher transcript levels of RAGE and S100B in advanced staged melanoma patients. The contribution of RAGE in the pathophysiology of melanoma has not been well studied. Based on previous reports, we hypothesized that RAGE, when over-expressed in melanoma cells, promotes melanoma progression. To study the pathogenic role of RAGE in melanoma, a primary melanoma cell line, WM115, was selected and stably transfected with full length RAGE (FL_RAGE) to generate a model cell line over-expressing RAGE (WM115_RAGE). WM266, a sister cell line of WM115, originated from a metastatic tumor of the same patient was used as a metastatic control cell line in the study. After assessing the expression levels of RAGE in the transfected cells, the influence of RAGE on their cellular properties was examined. An enhanced motility but suppressed proliferation of WM115 cells was found after RAGE over-expression, these properties could be reversed upon suppression of RAGE in these cells. We next explored the mechanisms of RAGE induced changes in cell proliferation and migration in WM115_RAGE cells and found a significant upregulation in S100B protein in the WM115_RAGE melanoma cells compared to the MOCK cells. However, S100B suppression produced no effect on WM115_RAGE cells motility. Furthermore, expression of tumor suppressor p53 protein, which is one of the target proteins of S100B, was found to be significantly reduced in WM115 cells after RAGE over-expression. We also investigated the effect of RAGE over-expression on melanoma tumor growth and deciphered the downstream signaling involved. We found a significantly larger tumor growth rate of the WM115_RAGE cells compared to the control cells. S100B, S100A4, S100A6 and S100A10 proteins that are relevant in melanoma pathophysiology, were found to be upregulated in WM115_RAGE tumors compared to MOCK tumors. Moreover, enhanced AKT and ERK signal activation was observed in WM115_RAGE tumors as compared to MOCK tumors. Finally, anti-RAGE antibody treatment significantly suppressed tumor growth, which could be further enhanced by combining the antibody with the chemotherapeutic drug dacarbazine.