Though general anesthetics have now been used clinically for well over a century, both their mechanisms of action as well as the nature of any potentially neurotoxic side effects remain elusive. With roughly 234 million people undergoing surgery each year worldwide, it remains imperative that any potentially deleterious effects of anesthetics be investigated and addressed. The issue of anesthetic- induced neurotoxicity in certain subsets of patients has continued to garner attention over the past decade, as more pre-clinical and clinical studies released are suggesting that inhalational and intravenous anesthetics may both cause and mitigate existing significant neuropathology. Pre-clinically, both cell-culture and animal studies suggest that anesthetics may cause neuroapoptosis, caspase activation, neurodegeneration, β-amyloid protein (Aβ) accumulation and oligomerization, and ultimately, deficits in neurocognition. Interestingly, however, newer data suggest that certain volatile anesthetics, such as desflurane, may have a less harmful neurotoxic profile compared to others in the pre-clinical and clinical settings. Continued pre-clinical investigation may have significant impact on clinical practice in the near future. Clinically, recent studies have raised awareness that exposure to general anesthetics during childhood may be associated with an increased risk for subsequent deficits in learning, memory, and cognition. Furthermore, retrospective studies continue to allude to the potential effects of surgery and anesthesia on cognitive trajectory, and more specifically, post-operative cognitive dysfunction (POCD) in the elderly. Studies to date regarding both of these clinical topics, however, are fraught with confounders, and many are underpowered statistically. The aim of this review is to examine the current data (both pre-clinical and clinical) on anesthetic-induced neurotoxicity and argue that further data are needed to either support or refute the potential connection between anesthetics and neurotoxicity.