The use of enzyme polymorphisms for evolutionary and population genetic investigations has greatly facilitated the study of genetic structure both within and between species. Despite their utility as genetic markers, fundamental problems concerning the adaptive nature of enzyme variation have remained refractory to investigation. Numerous indirect statistical studies give support to the notion that enzyme polymorphisms are subject to selection, but direct evidence for selection is rare. Notable exceptions are the alcohol dehydrogenase (ADH) and the amylase polymorphisms in Drosophila melanogaster which have been intensively investigated under controlled environments and with randomized genetic backgrounds (for ADH see Gibson, 1970; Van Delden et al., 1975; Oakeshott, 1976; Cavener and Clegg, 1978; and Cavener, 1979; for amylase see Dejong et al., 1972; Hickey, 1977). In the case of both ADH and amylase the specific substrates of the enzymes were used in high concentrations in experimental populations to induce selection. Complimentary to these population experiments, in vitro kinetic differences have been demonstrated between the alternative allozymes and these differences appear to be consistent with the direction of gene frequency change observed in cage populations. It can be argued that the ADH and amylase polymorphisms are exceptional because they are involved in the processing of external substrates. In an effort to determine the validity of this view and to investigate adaptation at the biochemical level, we have chosen a somewhat different approach based upon the elementary proposition that metabolism is a closely integrated process. Because of the coordinated nature of biochemical pathways, a perturbation introduced at one point is likely to have manifold effects. Thus we have focused upon the manipulation of simple environmental factors (e.g., alcohol) and we have attempted to trace the genetic consequences arising from processing high levels of the stress factor. We have chosen to investigate adaptation to high concentrations of ethanol in Drosophila melanogaster. This is not an artificial choice because the major food resource of D. melanogaster is fermenting fruit which contains moderate to high concentrations of ethanol. Indeed, D. melanogaster has actually been found to undergo a part of its life cycle on floating