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More than 40years ago, the endogenous opioids were first described. Their role as important neuromodulators of pain and their influence on a variety of neuroendocrine control systems within the central nervous system has been recognized. More recently, endogenous opioids and their receptor have been identified in a variety of reproductive and non-reproductive tissues outside the central nervous system. What role the opioid system plays in these peripheral tissues and organs is not completely understood and thus the subjects of current research. In the central nervous system, endogenous opioids inhibit pulsatile Gonadotropin Releasing Hormone (GnRH) release, affecting the release of gonadotropins from the pituitary, and thus mediating stress response within the central nervous-pituitary-gonadal axes in both women and men-Peripherally, endogenous opioids have been demonstrated to be present-among other organs-in the pancreas and in the ovary, where they are produced by granulosa cells and may influence oocyte maturation. In men, endogenous opioids play a role in sperm production within the testis. Opioid antagonists such as naltrexone have been used to restore cyclicity in women through improvement in insulin resistance, GnRH-pulsatility and hyperandrogenemia stemming from specific pathophysiological conditions such as hypothalamic amenorrhea, polycystic ovarian syndrome, hyperinsulinemia, ovarian hyperstimulation syndrome. Opioid antagonists have also been used to treat male sexual disorders and male infertility. In summary, endogenous opioids exert a variety of actions within the reproductive system which are reviewed in this chapter., (© 2019 Elsevier Inc. All rights reserved.)