Consequences of directional selection on metabolic flux are explored in models for which variation in flux among individuals is generated by segregation of allelic variants at enzyme activity loci. The pattern of selection response is strongly affected by the presence of genetic dominance and epistasis, which are automatically generated in metabolic systems. The expected magnitudes of dominance and epistasis effects on flux are evaluated. Small differences in enzyme activity generate little dominance, but a null allele will tend to be recessive for the pathway in which it occurs and for metabolically distant pathways. Epistasis is found to be greatest in short pathways in which large differences in enzyme activity occur. Under divergent artificial selection asymmetrical responses can occur due to the presence of directional dominance and epistasis, and lead to departures from the classic infinitesimal model of quantitative genetic variation. The effects of epistasis and dominance are in opposite directions, however, and partially cancel each other out in a diploid population.