General anaesthesia is usually considered to safely induce a reversible brain state allowing the performance of surgery under optimal conditions. An increasing number of clinical and experimental observations, however, suggest that anaesthetic drugs, especially when they are administered at the extremes of age, can trigger long-term morphological and functional alterations in the brain. Here, we review available mechanistic data linking general-anaesthesia exposure to impaired cognitive performance in both young and mature nervous systems. We also provide a critical appraisal of the translational value of animal models and highlight the important challenges that need to be addressed to strengthen the link between laboratory work and clinical investigations in the field of anaesthesia-neurotoxicity research.