Awake craniotomy is routinely used in patients undergoing epilepsy surgery or surgery on eloquent areas of brain. Awake craniotomy allows for optimal lesion resection with minimal postoperative neurologic dysfunction. This chapter presents a case study of a 27-year-old right-handed male with a history of psychotic depression who worked as a baggage handler at a local airline. The primary concerns of the anesthesiology team were (1) preoperative airway assessment and management in the event of intraoperative airway obstruction, (2) intraoperative pain management, and (3) close monitoring for signs of seizure or neurologic decline. Modern use of awake craniotomies began with the introduction of propofol and subsequently dexmedetomidine. Careful patient selection and preoperative consideration of potential contraindications, the use of scalp blocks, improved anesthetic agents, and clear communication among members of the patient's care team will minimize many potential complications and improve patient outcome and satisfaction.