The steady rise in opioid users and abusers has uncovered multiple detrimental health consequences of perturbed opioid receptor signaling, thereby creating the need to better understand the biology of these systems. Among endogenous opioid networks, μ-receptors have received special attention due to their unprecedented biological complexity and broad implications in homeostatic functions. Here, we review the origin, molecular biology, and physiology of endogenous opioids with a special focus on μ-opioid receptor networks within the endocrine system. Moreover, we summarize the current evidence supporting an involvement of the latter in regulating distinct endocrine functions. Finally, we combine these insights to present an integrated perspective on μ-opioid receptor biology and provide an outlook on future studies and unresolved questions in this field.