Alcohol use and abuse appear to be related to neuroadaptive changes at functional, neurochemical, and structural levels. Acute and chronic ethanol exposure have been shown to modulate function of the activity-dependent gene transcription factor, cAMP-responsive element binding (CREB) protein in the brain, which may be associated with the development of alcoholism. Study of the downstream effectors of CREB have identified several important CREB-related genes, such as neuropeptide Y, brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and corticotrophin-releasing factor, that may play a crucial role in the behavioral effects of ethanol and molecular changes in the specific neurocircuitry that underlie both alcohol addiction and a genetic predisposition to alcoholism. Brain chromatin remodeling due to histone covalent modifications may also be involved in mediating the behavioral effects and neuroadaptive changes that occur during ethanol exposure. This review outlines progressive neuroscience research into molecular and epigenetic mechanisms of alcoholism.