The study explores the hormonal basis of sex differences in anesthetic sensitivity, revealing that female mice are more resistant to volatile anesthetics than males. This resistance is bidirectionally modulated by testosterone, with castration increasing resistance and testosterone administration enhancing sensitivity. Conversion of testosterone to estradiol via aromatase partially explains this effect. In humans, females also show increased resistance to anesthetics, though EEG does not detect sex differences. Whole-brain c-Fos imaging shows fewer active neurons in female hypothalamic sleep-promoting regions, suggesting a hypothalamic origin of the resistance. Despite behavioral differences, EEG and ECoG do not reflect sex differences in anesthetic sensitivity. These findings indicate that sex differences in anesthetic sensitivity are evolutionarily conserved and not captured by conventional EEG measures. The resistance may explain the higher incidence of unintended awareness in females under general anesthesia. The study highlights the need for further research into the mechanisms underlying these sex differences and their implications for clinical practice.The study explores the hormonal basis of sex differences in anesthetic sensitivity, revealing that female mice are more resistant to volatile anesthetics than males. This resistance is bidirectionally modulated by testosterone, with castration increasing resistance and testosterone administration enhancing sensitivity. Conversion of testosterone to estradiol via aromatase partially explains this effect. In humans, females also show increased resistance to anesthetics, though EEG does not detect sex differences. Whole-brain c-Fos imaging shows fewer active neurons in female hypothalamic sleep-promoting regions, suggesting a hypothalamic origin of the resistance. Despite behavioral differences, EEG and ECoG do not reflect sex differences in anesthetic sensitivity. These findings indicate that sex differences in anesthetic sensitivity are evolutionarily conserved and not captured by conventional EEG measures. The resistance may explain the higher incidence of unintended awareness in females under general anesthesia. The study highlights the need for further research into the mechanisms underlying these sex differences and their implications for clinical practice.