Identifying new drugs and targets for melanoma therapy is critical, considering that melanoma, the most dangerous form of skin cancer, is resistant to currently available therapeutics. Much work has been focused on finding novel drugs and exploring different treatment options that could increase the overall survival of patients. In our laboratory we have developed mouse models to study melanoma. We discovered that aberrant expression of metabotropic glutamate receptor 1 (Grm1) in melanocytes promotes melanoma development in vivo. Grm1 is a seven transmembrane domain G-protein coupled receptor that is normally expressed and functional in the central nervous system. The natural ligand of Grm1 is glutamate. Signaling by the major neurotransmitter glutamate has been well characterized in neuronal cells; however glutamate signaling in other tissues is not well understood. We demonstrated that Grm1 signaling in melanoma cells is mediated by the Ras/Raf/MEK/ERK pathway, one of the major pathways previously shown to be activated in human melanoma cells. Based on these earlier studies and results from our recent work, we predict that inhibition of Grm1 signaling and its downstream cascade may potentially provide new, effective therapies for melanoma patients. In this review, we propose several attractive targets.