GPR39 is a constitutively active orphan G-protein-coupled receptor capable of increasing serum-response-element mediated transcription. We found GPR39 to be upregulated in a hippocampal cell line resistant against diverse stimulators of cell death and show that its overexpression protects against oxidative and endoplasmic reticulum stress, as well as against direct activation of the caspase cascade by Bax overexpression. In contrast, silencing GPR39 rendered cells more susceptible to cell death. An array analysis of transcripts induced by GPR39 revealed upregulation of RGS16 (inhibitor of G-protein signaling 16), which suggested coupling to Ga13 and induction of serum-response-element mediated transcription by the small GTPase RhoA. In line with this, co-expression of GPR39 with RGS16, dominant-negative RhoA or SRF abolished cell protection, whereas overexpression of serum-response factor SRF protected. Further downstream the signaling cascade, GPR39 overexpression leads to increased secretion of the cytoprotective pigment epithelial derived growth factor PEDF. Medium conditioned by cells overexpressing GPR39 contained fourfold more PEDF and when stripped off it lost most but not all of its protective properties. We conclude that GPR39 is a novel inhibitor of cell death, which might represent a therapeutic target with implications for processes involving apoptosis and ER stress like cancer, ischemia/reperfusion injury, and neurodegenerative disease.