Opioids are defined as all drugs, both natural and synthetic, with morphine-like action. Opium contains morphine and other opioid alkaloids, such as thebaine and codeine. Opioids are the most powerful pain relievers known to man. Similarly to other drugs of abuse, the self-limited, controlled use of opioids is accompanied by a lack of withdrawal symptoms and limited pathology. However, opioid addiction remains a serious problem worldwide, and the diversion of opioid pain medications from their prescribed use to abuse has reached epidemic-like levels. Opioids have very powerful psychotropic effects. They relieve not only physical pain but also emotional pain, thus forming their main behavioral mechanism of action. Opioid intoxication from intravenous or smoked use is characterized by different stages that include the rush, nod, high, and being straight. Opioid withdrawal is characterized by very severe motivational and physical symptoms. Motivational signs can begin with a single administration. Protracted abstinence is characterized by powerful craving that derives from both conditioned positive and negative reinforcement and a hypersensitivity to pain and stress. Much is known about the neurobiological substrates for the acute reinforcing effects of opioids. At the neurocircuitry level, neural elements in the region of the ventral tegmental area and nucleus accumbens are important. At the cellular level, evidence exists for a disinhibitory effect of opioids via glutamatergic or GABAergic interneurons, both in the nucleus accumbens and ventral tegmental area. At the molecular level, the μ opioid receptor is the subtype most critical for the acute reinforcing effects of opioids. μ Opioid receptor knockout mice do not show opioid dependence or withdrawal. During the development of dependence on opioids, major between-system changes occur at the level of the ventral tegmental area and nucleus accumbens that contribute to the motivational effects of withdrawal. Chronic morphine produces a sensitized aversive response to opioid antagonists in the extended amygdala, with recruitment of norepinephrine and CRF activity. A decrease in the neuronal firing of dopamine neurons in the ventral tegmental area occurs during withdrawal that may be mediated by the increased release of GABA and decreased release of glutamate. Opioid and dopaminergic mechanisms are involved in opioid-induced (primed) reinstatement, glutamate is involved in cue-induced reinstatement, and the brain stress systems (CRF and norepinephrine) are involved in stress-induced reinstatement. All of these changes may contribute to the decreased reward system activity and increased stress system activity associated with opioid dependence and the allostatic molecular changes that drive craving during protracted abstinence associated with opioid dependence.