It is possible to define a strategy for experimentally demonstrating that natural selection acts directly on a particular polymorphic locus, rather than on other loci in linkage disequilibrium with it. This strategy has been applied to the alcohol dehydrogenase polymorphism of Drosophila melanogaster and has provided very strong evidence that the polymorphism is directly subject to selection. It is equally applicable to other polymorphisms and offers the hope of resolving the long-standing debate about the causes of enzyme variation.