Gonadal hormones affect not only reproductive system but also virtually all cells in the body. For example estrogen promotes nociception via their effects on the peripheral vessels by releasing of vasoactive mediator, e.g., prostacyclin and NO, causes vasodilation, or spasmogenic response. In spinal cord, estrogen reduces pain through the activation of κ -opioid analgesic system. Nevertheless, gonadal hormones affect cognitive function and emotion through their actions on the cholinergic system in the brain. Gonadal hormones also play an active role in modulating the balance of endogenous opioids and monoamines such as norepinephrine-, acetylcholine- and serotonin-mediated action. The exact mechanisms by which gonadal hormones influence pain perception are far from being fully elucidated. Delving deeper into the sex differences in each body region would certainly disclose some secrets.