The G protein-coupled receptors (GPCRs) constitute a large superfamily of seven transmembrane-spanning receptors that are activated by several classes of ligands, including bioactive lipids. GPCRs are attractive therapeutic targets for the treatment of human diseases, as they finely regulate a wide array of cellular functions. In this minireview, we summarized what is currently known about the G protein-coupled receptor GPR31/12-HETER. We highlighted, in particular, its structural similarity with human homologs, the biological functions of its recognized ligand 12(S)-hydroxyeicosatetraenoic acid (HETE), an arachidonic acid metabolite, and the role that GPR31/12-HETER-mediated signals play in cancer cell growth, invasion and metastasis, and in liver ischemia–reperfusion (IR) injury. Recent studies shed light and interest on the 12(S)-HETE/GPR31/12-HETER-activated signaling pathways and functions. The full spectrum of GPR31/12-HETER-mediated biological functions has yet to be characterized. Further studies are needed to identify other potential ligands, i.e. other than 12(S)-HETE. Another important remaining question is whether the multiple 12(S)-HETE-induced biological activities, including its role in diabetes, neurodegeneration, neuroprotection, and platelet function, occur via GPR31/12-HETER and/or involve the activation of other receptor molecules and pathways.