Synopsis The regulation of gene product activity allows cells to efficiently cope with various tasks under varying conditions. Given that, one may have expected that striving for efficiency would cause genetically similar cells to have similar regulation. However, in reality, high variations in gene expression levels are detected between different strains and even between genetically identical cells taken from the same culture. What are the driving forces that lead to expression divergence in some genes and conserved expression in others? To address this question, the authors study the conservation of regulation in yeast metabolism, using a computational model. They find that genes coding for reactions whose flux rates are narrowly constrained by the cellular need to maximize growth rate tend to have strictly conserved regulation and expression. However, when a wide range of flux rates is compatible with high cellular growth rates, the corresponding regulation and expression patterns are free to diverge. Furthermore, enzymes that participate in a large number of alternative metabolic behaviors tend to be encoded by genes with a highly conserved sequence. Taken together, these findings support the hypothesis that maintaining large variability in the overall expression and metabolic repertoire of the cell is under marked evolutionary selection.