There has been considerable recent interest in deciphering the adaptive properties underlying the structure and function of metabolic networks. Various features of metabolic networks such as the global topology, distribution of fluxes, and mutational robustness, have been proposed to have adaptive significance and hence reflect design principles. However, whether evolutionary processes alternative to direct selection on the trait under investigation also play a role is often ignored and the selection pressures maintaining a given metabolic trait often remain speculative. Some systems-level traits might simply arise as by-products of selection on other traits or even through random genetic drift. Here, we ask which systems-level aspects of metabolism are likely to have adaptive utility and which could be better explained as by-products of other evolutionary forces. We conclude that the global topological characteristics of metabolic networks and their mutational robustness are unlikely to be directly shaped by natural selection. Conversely, models of optimal design revealed that various aspects of individual pathways and the behavior of the whole network show signs of adaptations, even though the exact selective forces often remain elusive. Comparative and experimental approaches, which so far have been relatively rarely employed, could help to distinguish between alternative adaptive scenarios. © HFSP Publishing.