In the early days of modern neurological surgery, the inconveniences and potential dangers of general anesthesia by chloroform and ether using the so-called "open-drop technique" led to the quest for alternative methods of anesthesia. Besides preventing the feared side effects, the introduction of regional anesthesia revealed another decisive advantage over general anesthesia in neurosurgery: While intraoperative direct cortical stimulation under general anesthesia could only delineate the motor area (by evocation of contralateral muscular contraction), now, the awake patients were able to report sensations elicited by this method. These properties advanced regional anesthesia to the regimen of choice for cranial surgeries in the first half of the 20th century. While technical advances and new drugs led to a progressive return to general anesthesia for neurosurgical procedures, the use of regional anesthesia for epilepsy surgery has only decreased in recent decades. Meanwhile, awake craniotomies regained popularity in oncologically motivated surgeries, especially in craniotomies for diffuse low-grade gliomas. Intraoperative mapping of brain functions using electrical stimulation in awake patients enables not only for increased tumor removal while preserving the functional status of the patients but also opens a window to cognitive neuroscience. Observations during such interventions and their correlation with both pre - and postoperative neuropsychological examinations and functional neuroimaging is progressively leading to new insights into the complex functional anatomy of the human brain. Furthermore, it broadens our knowledge on cerebral network reorganization in the presence of disease-with implications for all disciplines of clinical neuroscience.