Microorganisms employ a wealth of gene regulatory mechanisms to adjust their growth programs to variations in the environment. It was pointed out long ago [Savageau M (1977) Proc Natl Acad Sci USA 74: 5647-5651] that the particular mode of gene regulation employed may be correlated with the "demand" on the regulated gene, i.e., how frequently the gene product is needed in its natural habitat. An evolutionary "use-it-or-lose-it" principle was proposed to govern the choice of gene regulatory strategies. Here, we examine quantitatively the forces selecting for and against two opposing modes of gene regulation, in the context of an evolutionary model that takes genetic drift, mutation, and time-dependent selection into account. We consider the effect of time-dependent selection, with periods of strong selection alternating with periods of neutral evolution. Using a variety of analytical methods, we find the effective population size and the typical time scale of environmental variations to be key parameters determining the fitness advantage of the different modes of regulation. Our results support Savageau's use-it-or-lose-it principle for small populations with long time scales of environmental variations and support a complementary "wear-and-tear" principle for the opposite situation.