Alcohol is widely used in society for both its social and medicinal benefits. It is readily derived in nature from fermentation. Early in human history, individuals learned to exploit the fermentation process to produce beverages and tonics. Alcohol is a sedative hypnotic that has euphoric and disinhibitory effects, explaining why some see it as a “social lubricant.” Many of the alleged stimulant effects of alcohol probably result from such disinhibitory effects, which define its behavioral mechanism of action. As the dose of alcohol increases to levels associated with binge drinking, however, disinhibition gives way to motor impairment, muscular incoordination, impairments in reaction time, impairments in judgment, impairments in sensory processing, and impairments in cognitive function – all behavioral effects that contribute to its behavioral toxicity. Binge drinking is defined as four drinks (in females) or five drinks (in males) over a 2 hour period. The chronic use of alcohol can lead to alcoholism or Dependence on Alcohol as defined by the ICD-10 and Substance Use Disorder on Alcohol as defined by the DSM-5. Numerous other medical diseases can also result from chronic alcohol use, ranging from cirrhosis of the liver to heart disease and pancreatitis to Wernicke–Korsakoff syndrome. All-to-frequent serious pathologies produced by drinking during pregnancy include fetal alcohol syndrome and fetal alcohol spectrum disorder. During the binge/intoxication stage, the neurobiological mechanism of action for the acute reinforcing effects of alcohol involves prominent actions on the GABAergic system and activation of some of the same reward neurotransmitters implicated in the actions of psychostimulants and opioids, including dopamine and opioid peptides. For a colorful representation of the symphony of alcohol’s effects, see Figure 6.23. At the cellular level, alcohol has been shown to have specific synaptic effects, with very low doses of alcohol enhancing GABAergic neurotransmission and inhibiting glutamate neurotransmission, actions that show neuroadaptations during abstinence. Alcohol also interacts with second-messenger systems, notably the actions of protein kinases that can change the sensitivity of ligand-gated receptors or enhance gene transcription. Molecular genetic and knockout studies have confirmed some of the more powerful neuropharmacological effects that involve actions at μ opioid and neuropeptide Y systems but also have identified specific genes that are implicated in alcohol preference and excessive drinking. During the withdrawal/negative affect stage, abstinence from chronic alcohol, similar to other drugs of abuse, disrupts reward neurotransmitter function, such as dopamine, opioid peptides, and GABA, and recruits the brain stress CRF system and dysregulates the brain anti-stress neuropeptide Y system, all of which appear to contribute to motivational withdrawal and excessive drinking during dependence. These effects have been localized to the ventral striatum and extended amygdala, providing support for the role of the extended amygdala in the acute and chronic motivational effects of alcohol in the development of dependence. During the preoccupation/anticipation stage, disruptions in reward function and the sensitization of brain stress systems persist into protracted abstinence. Animal models of relapse have provided evidence of a role for opioid peptides, dopamine, and glutamate in cue-induced reinstatement and CRF in stress-induced reinstatement. The challenge for future research is to identify how receptor proteins, neurons, and circuits convey the vulnerability to excessive and compulsive drinking associated with substance use disorders on alcohol.