Although the glutamatergic system usually functions in the CNS, expression has been observed in non-neuronal tissues and a subset of cancers. Metabotropic glutamate receptors (mGlus) are highly "druggable" GPCRs and thus a priority for validation as therapeutic targets. We have previously reported that the aberrant expression of mGlu1 is sufficient to induce spontaneous melanoma development in vivo. We isolated and characterized several stable mGlu1-mouse melanocytic clones and demonstrated that these clones are transformed and tumorigenic. We hypothesize that expression of mGlus may not be uncommon in the pathogenesis of tumors other than melanoma, and that activity of an otherwise normal glutamate receptor in an ectopic cellular environment involves signaling pathways which dysregulate cell growth, ultimately leading to tumorigenesis. As most human cancers are of epithelial origin (carcinomas), in this review, the possibility that mGlu1 could function as a complete oncogene and transform epithelial cells is also discussed.