After many years of limited therapeutic opportunities, the treatment of type 2 diabetes has become more target and pathophysiologically driven. A typical example is represented by the development of the dipeptidyl peptidase-4 (DPP-4) inhibitors, allowing for more physiological regulation of the endocrine pancreas and leading to a previously unmet risk-to-benefit balance. Vildagliptin, one of the earliest DPP-4 inhibitors, has been tested across the entire spectrum of type 2 diabetes and has been in clinical use for 20 years. This publication critically reviews the main steps in the clinical development of this agent.