Regional anesthesia of the peripheral nerves has evolved considerably over the past two decades. It is now widely practiced and provides considerable benefits to patients in the perioperative period. Peripheral regional anesthesia has an excellent safety profile, with the overall incidence of persistent neurologic injury between 0.01 and 0.1%. The range reflects the challenge in studying such an infrequent outcome, as well as the difficulty in distinguishing between neurologic injuries due to the regional technique versus those secondary to other perioperative causes. Exact mechanisms of neurologic injury due to peripheral nerve blockade are incompletely understood, but evidence suggests that mechanical trauma, ischemia, chemical neurotoxicity of injectates, and physical nerve entrapment may all be implicated. Strategies targeting these mechanisms have been proposed to reduce nerve injury and are currently undergoing investigation.