Nalmefene is an opioid-receptor modulator with antagonistic effects at the μ- and δ-opioid receptors, with partial antagonism only at the κ-opioid receptor. Nalmefene has been studied in alcohol use disorder since the 1990s. Initial studies were conducted in the United States, followed by a series of large-scale studies in Europe followed by a study in Japan. In the European and Japanese studies, nalmefene was used in an as-needed fashion, i.e., in case alcohol consumption was anticipated. Compared to the placebo condition, in the European and Japanese studies, nalmefene reduced the number of heavy drinking days and in some studies also total alcohol consumption significantly. Adverse events were of mild to moderate nature and transient. Some pharmacological interactions with UGT inhibitors/inducers should be considered.