General anesthetics are highly lipid soluble and can dissolve in every membrane, penetrate into organelles and interact with numerous cellular constituents. Their actions have long been considered rapid and fully reversible, with the pharmacodynamic time course of anesthesia dictated solely by the pharmacokinetic profiles of anesthetic uptake and elimination. But recent laboratory data call for a cautious reassessment of this assumption. In the last decade, it has become apparent that anesthetics can affect gene expression, protein synthesis and processing, and cellular function in poorly understood ways that provide plausible biochemical substrates for durable long-term effects in a number of tissues. While in most patients physiological homeostasis is restored soon following general anesthesia, anesthetics have potentially profound and long-lasting effects that, in animal models, appear particularly consequential in specific developmental periods and pathophysiological contexts. Could a class of drugs employed for many decades without evidence of long-term damage have insidious and heretofore unrecognized neurotoxic effects? Here we critically evaluate available scientific evidence for general anesthetic ‘neurotoxicity’ and the potential clinical implications. Since the scope of this clinical commentary is limited, numerous deserving laboratory investigations could not be mentioned in this focused overview. Our goal as physician-scientists not directly involved in this area of research is to summarize the diverse directions of research in this field, while highlighting the limitations of existing data with respect to clinical practice in order to provide the reader with a rational platform for discussions with colleagues and patients. The barriers that must be overcome to permit clinical translation of the available laboratory research are emphasized, along with the need for further research, as recently highlighted in a consensus statement by a group including authoritative researchers in this field.1 As with any emerging field of research, new evidence continues to accrue such that conclusions are by necessity preliminary and will require frequent reappraisal.