Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gα signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract, or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQ oncogene. We found that GNAQ, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation, and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and Braf expressing melanocytes. Hence, our studies reveal the flip side of Gα signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQ oncogene could suggest novel therapies for and mutant melanomas.