Neural blockade remains a key diagnostic and treatment modality for interventional pain management. Most of the techniques used in chronic and acute pain management today evolved out of different techniques used by surgeons and anesthesiologists alike to facilitate surgical procedures and alleviate intra- and postoperative pain. Many of these techniques were developed and introduced into medical practice during the late 19th and early 20th centuries and were only recently challenged by increasing neurophysiologic understanding and modern imaging studies. A brief historical overview of the topic of neural blockade as well as current knowledge of mechanisms and clinical aspects of nerve blocks are considered. The review focuses on relevant aspects of anatomy, cell physiology, molecular mechanisms of effect, and clinical aspects of nerve blocks.