Depression is more prevalent in women than in men, with global prevalence rates being 1.7 times higher. This difference is not primarily due to social or economic factors but may be linked to biological sex differences. Women experience depression more frequently, especially during puberty, premenstrual, postpartum, and perimenopause, which are associated with hormonal changes. Studies suggest that estrogen plays a protective role against depression, and its decline may increase the risk. However, men also have lower rates of depression, possibly due to testosterone converting to estrogen in the brain, which may provide some protection. The genetic difference between men and women, with women having two X chromosomes, may also contribute to the sex difference in depression risk. While social factors may play a role, biological factors such as hormonal fluctuations and brain differences are likely key contributors. Research indicates that estrogen receptor-selective ligands could offer targeted treatment for depression without the side effects of estrogen therapy. Despite these findings, the female:male depression ratio has not changed significantly in Western societies, suggesting that social attitudes alone may not be sufficient to reduce the disparity. Further research is needed to understand the biological mechanisms underlying the sex difference in depression and to develop more effective, sex-specific treatments.Depression is more prevalent in women than in men, with global prevalence rates being 1.7 times higher. This difference is not primarily due to social or economic factors but may be linked to biological sex differences. Women experience depression more frequently, especially during puberty, premenstrual, postpartum, and perimenopause, which are associated with hormonal changes. Studies suggest that estrogen plays a protective role against depression, and its decline may increase the risk. However, men also have lower rates of depression, possibly due to testosterone converting to estrogen in the brain, which may provide some protection. The genetic difference between men and women, with women having two X chromosomes, may also contribute to the sex difference in depression risk. While social factors may play a role, biological factors such as hormonal fluctuations and brain differences are likely key contributors. Research indicates that estrogen receptor-selective ligands could offer targeted treatment for depression without the side effects of estrogen therapy. Despite these findings, the female:male depression ratio has not changed significantly in Western societies, suggesting that social attitudes alone may not be sufficient to reduce the disparity. Further research is needed to understand the biological mechanisms underlying the sex difference in depression and to develop more effective, sex-specific treatments.