In search of new treatments for obesity and type 2 diabetes (“diabesity”), we have de-orphanized GPR119, a G_αS protein-coupled receptor whose expression is localised predominantly in the pancreas (β-cells) and gastrointestinal tract (L-cells). We recently reported oleoylethanolamide (OEA) to be the most active endogenous ligand thus far identified¹. OEA has been described as a peripherally-acting agent which reduces food intake and body weight gain in rodent models, leading us to hypothesise that GPR119 may represent a novel and attractive drug discovery target. We have therefore developed several biological tools, including a yeast reporter system as a high-throughput assay, and have identified novel, selective, orally-available GPR119 agonists. Such agents could provide attractive new oral therapies for type 2 diabetes and obesity, offering significant improvements in metabolic parameters such as glucose tolerance, as well as body weight loss. The results of our studies with representative synthetic small-molecule agonists in various cell systems and in rodent models of diabetes and obesity will be presented.