The urgent need for medical treatments of alcohol use disorders has motivated the search for novel molecular targets of alcohol response. Most studies exploit the strengths of lab animals without considering how these and other species may have adapted to respond to alcohol in an ecological context. Here, we provide an evolutionary perspective on the molecular and genetic underpinnings of alcohol consumption by reviewing evidence that alcohol metabolic enzymes have undergone adaptive evolution at 2 evolutionary junctures: first, to enable alcohol consumption accompanying the advent of a frugivorous diet in a primate ancestor, and second, to decrease the likelihood of excessive alcohol consumption concurrent with the spread of agriculture and fermentation in East Asia. By similarly considering how diverse vertebrate and invertebrate species have undergone natural selection for alcohol responses, novel conserved molecular targets of alcohol are likely be discovered that may represent promising therapeutic targets.