Most organisms, however evolutionarily distant, contain a set of common metabolites. But their intracellular concentrations are unique to each individual species. This metabolic identity of an organism is the consequence of quantitative differences in relevant enzyme properties and their associated regulation. Features of metabolic regulation are unique to each organism—often within a closely related group of organisms. It is becoming increasingly clear that the concept of unity in biochemistry does not always extend to metabolic pathway control and enzyme regulation. Historically, metabolic regulation and control of enzyme activity have developed as closely related phenomena. What then is the justification to place regulation of enzyme activity here in “Frontiers in Enzymology”? Over the years, molecular developments in biology have outshone the progress made in physiological and system-level understanding of organisms. While the basic principles of enzyme/metabolic regulation may have been uncovered, novel modes of regulation continue to be discovered. Nature continues to surprise us with original ways of regulating enzyme activity. The novelty may be in the conceptual mechanism, or the regulatory ligands involved. For instance, fructose-2,6-bisphosphate as a regulator of glycolysis (at the phosphofructokinase step) was discovered much later (in early 1980s)—many decades after the complete description of glycolytic enzymes (Hers and Hue 1983). In this sense, the topic of regulation of enzyme activity will always be at the frontiers of enzymology.