Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its efficacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specific neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, first approved in France in 1989, received FDA approval in 2004. However, the beneficial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater efficacy but a variety of adverse effects. In addition to the identification of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment efficacy and adverse effects is used to personalize treatment.