The influence of sex and gender on anesthesia and analgesic therapy remains poorly understood, nevertheless the numerous physiological and pharmacological differences present between men and women. Although in anesthesiology sex-gender aspects have attracted little attention, it has been reported that women have a greater sensitivity to the non-depolarizing neuroblocking agents, whereas males are more sensitive than females to propofol. It has been suggested that men wake slower than women after general anesthesia and have less postoperative nausea and vomiting. Sexual hormones seem to be of importance in the onset of differences. Nevertheless, in the last years, sex-gender influences on pain and analgesia have become a hot topic and data regarding sex-gender differences in response to pharmacologic and non-pharmacologic pain treatments are still scanty, inconsistent, and non-univocal. In particular, females seem to be more sensitive than males to opioid receptor agonists. Women may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. Evidently, there is an obvious need for more research, which should include psychological and social factors in experimental preclinical and clinical paradigms in view of their importance on pain mechanism, in order to individualize analgesia to optimize pain relief.