Type 2 diabetes (T2D) is a multifactorial disease with multiple etiology, characterized by chronically elevated blood glucose levels. Although the reduction of pancreatic β-cell functional mass, associated or not with peripheral insulin resistance, is recognized as the main etiopathogenetic factor leading to the onset of T2D, the dysregulation of glucose metabolism is actually the result of multi-organs alterations, including skeletal muscle and adipose tissue dysfunction, hepatic insulin resistance, and incretin axis defects. Furthermore, the chronic elevation of blood glucose levels leads to the onset of systemic complications affecting many organs and tissues. Therefore, T2D is a multi-organ disease and future anti-diabetic drugs can no longer be considered simple hypoglycemic drugs: they should at least be able to restore β-cell functional mass, reduce peripheral insulin resistance, ensure adequate weight loss (when necessary), and exert cardio- and nephro-protective effects. In light of this, irisin, a hormone secreted by skeletal muscle in response to physical activity, should be remarked as a new promising anti-diabetes molecule, being able to exert beneficial effects on the various organs involved in the pathogenesis of T2D, in particular on pancreatic β-cells, liver, skeletal muscle, adipose tissue, and many of the organs affected by diabetes complications.