P2X7 receptors can be found in many tissues and organs, where they mediate several biological functions. This review summarizes the current knowledge about the role of this receptor in the pathogenesis of type 2 diabetes, in which the key clinical features are impaired insulin secretion and sensitivity, hyperglycemia, coexistence of other cardiovascular risk factors such as dyslipidemia and hypertension, and subclinical inflammation. The receptor modulates crucial pathways in the pancreatic islets (where it can either exert a trophic or detrimental action on β cells), and in the liver, in the adipose tissue and in the skeletal muscle, which are main sites of insulin resistance. P2X7 receptors also modulate a series of inflammatory responses that participate in the development of the microvascular complications of the disease. Potent and selective P2X7R blockers are available to be tested in Phase I/II clinical studies for the treatment of several chronic diseases, and it might be worthwhile to consider inclusion of patients with type 2 diabetes and its complications.