The prevalence of obesity and type 2 diabetes (T2D) is increasing worldwide, and these two metabolic disorders are closely linked. Lifestyle modification, including weight loss and exercise, are effective treatments for T2D, but, unfortunately, most patients are unsuccessful at maintaining durable weight reduction and recidivism is all too common. Therefore, safe and efficacious drugs are required for the successful treatment of T2D in a large proportion of patients. Targeting G protein-coupled receptors (GPCRs) in metabolic tissues — such as adipose tissue, liver, muscle, pancreatic islets, immune cells and the central nervous system — has emerged as a key target for current and future anti-diabetic compounds. This Opinion focuses on the potential of GPCRs as targets for the discovery of new drugs to successfully treat T2D.