The opioid system, consisting of mu, delta, and kappa receptors, is activated by endogenous opioids derived from proopiomelanocortin, proenkephalin, and prodynorphin. This system plays a crucial role in modulating hedonic responses and is modified by drug abuse. The review covers the anatomy of the opioid system in the brain, the effects of local pharmacological manipulation, gene knockout, and chronic drug exposure on opioid system genes. The opioid system is involved in natural reinforcement, such as food and sexual behaviors, and drug reinforcement, including opiates, non-opioid drugs, and ethanol. Key brain regions, such as the ventral tegmental area (VTA), nucleus accumbens (NAc), ventral pallidum (VP), amygdala (AMG), and hypothalamus, are highlighted for their roles in these processes. The review also discusses the interaction between opioid receptors and other neurotransmitter systems, such as dopamine and glutamate, in mediating reinforcement. Overall, the opioid system's role in addiction and its potential as a therapeutic target is emphasized.The opioid system, consisting of mu, delta, and kappa receptors, is activated by endogenous opioids derived from proopiomelanocortin, proenkephalin, and prodynorphin. This system plays a crucial role in modulating hedonic responses and is modified by drug abuse. The review covers the anatomy of the opioid system in the brain, the effects of local pharmacological manipulation, gene knockout, and chronic drug exposure on opioid system genes. The opioid system is involved in natural reinforcement, such as food and sexual behaviors, and drug reinforcement, including opiates, non-opioid drugs, and ethanol. Key brain regions, such as the ventral tegmental area (VTA), nucleus accumbens (NAc), ventral pallidum (VP), amygdala (AMG), and hypothalamus, are highlighted for their roles in these processes. The review also discusses the interaction between opioid receptors and other neurotransmitter systems, such as dopamine and glutamate, in mediating reinforcement. Overall, the opioid system's role in addiction and its potential as a therapeutic target is emphasized.