One current challenge in metabolic systems biology is to map out the regulation networks that control metabolism. From progress in this area, we conclude that non-transcriptional mechanisms (e.g. metabolite–protein interactions and protein phosphorylation) are highly relevant in actually controlling metabolic function. Furthermore, recent results highlight more functions of enzymes and metabolites than currently appreciated in genome-scale metabolic reconstructions, thereby adding another level of complexity. Combining experimental analyses and modeling efforts we are also beginning to understand how metabolic behavior emerges. Particularly, we recognize that metabolism is not simply a dull workhorse process but rather takes very active control of itself and other cellular processes, rendering true system-level understanding of metabolism possibly more difficult than for other cellular systems.