Cells compensate to perturbation through a multi-tiered regulatory response. To model this cross-talk, we coupled genomic, metabolomic, and fluxomic technologies to measure 5798 mRNAs, 111 metabolites, and 61 reaction fluxes in yeast under stress with and without global regulator Gcn4p. While mRNA expression was insufficient to directly predict the metabolite and flux responses, and vice versa, all three measurement types were better explained by a global network based model model of amino acid biosynthesis containing 134 molecules, 72 rates, and 245 interactions. These results underscore the importance of integrating both genomic, fluxomic, and metabolic information in large-scale cellular models.