General anesthesia-induced pharmacological protection of the central nervous system following injury has been under intense investigations during the past four decades. Indeed, if general anesthetics could provide therapeutic benefit in the event of hypoxia, ischemia or any other kinds of brain lesions, that would be of tremendous clinical importance. The potential for anesthesia-related brain protection, however, has been seriously challenged during the past 10 years. In fact, an increasing number of experimental and, more recently, clinical observations suggest that general anesthetics might exert unwanted, toxic effects on the brain especially when administered to young infants or to the elderly. Of utmost importance, recent data suggest that these same drugs could even have therapeutic effects in some psychiatric disorders. The goal of this review is to highlight these apparent contradictions. We will consider the available experimental evidence arguing for anesthetic-induced neuroprotection and highlight the lack of clinical studies supporting this notion. The biological rational for anesthesia neurotoxicity will then be explored together with existing experimental and clinical evidence in favor of this possibility. Finally, insights into the increasing number of both experimental and clinical data suggesting that general anesthetics, especially ketamine, support the therapeutic value of these drugs in major depressive disorders. When taken together, these seemingly contradictory observations suggest the intriguing possibility that general anesthetics could stand as valuable context-dependent modulators of neural plasticity.