Melanoma is the most malignant form of skin cancers that originated from melanocytes, the pigment cells in the skin. Early detection is the key for increased chance of survival, since currently there is no assuring therapeutic means for late stage melanoma. Animal models have been a valuable tool to understand human disorders and to identify new therapeutic targets for the treatments of a disease including melanoma. Previously, we reported on a transgenic mouse model with predisposition to melanoma development with 100% penetrance [37]. Subsequent studies identified the aberrant expression of metabotropic glutamate receptor 1 (Grm1) in melanocytes to be critical in the onset of melanoma. Confirmation of the etiological role of Grm1 in melanoma development was demonstrated in a second transgenic mouse line with Grm1 expression under the regulation of a melanocyte-specific dopachrome tautomerase (DCT) promoter [40].Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma. GRM1, a seven-transmembrane domain G-protein coupled receptor, is normally expressed and functional in neuronal cells and its ligand, glutamate, is the major excitatory neurotransmitter. MAPK has been shown by many investigators to be one of the key signaling pathways in human melanoma cell proliferation [45, 55]; We also showed that MAPK signaling cascade being the downstream target of activated GRM1 [47]. Furthermore, treatment of GRM1- expressing human melanoma cells with a GRM1-antagonist leads to a suppression of cell proliferation. Human melanoma cells released elevated levels of glutamate, implying a possible autocrine loop. Treatment of human melanoma cells with a GRM1-antagonist or an inhibitor of glutamate release, Riluzole, leads to a decrease in release of glutamate and suppression of cell growth. In vivo xenografts with human melanoma cells, when treated with Riluzole, resulted in an inhibition of tumor growth/progression. Taken together, these data suggest the pivotal role of glutamate signaling in human melanoma and imply the potential of a new target for melanoma therapy.