System-wide interactions in living cells and discovery of the diverse roles of transcriptional regulatory proteins that are mediator proteins with catalytic domains and regulatory subunits and transcription factors in the cellular pathways have become crucial for understanding the cellular response to environmental conditions. This review provides information for future metabolic engineering strategies through analyses on the highly interconnected regulatory networks inSaccharomyces cerevisiaeandPichia pastorisand identifying their components. We discuss the current knowledge on the carbon catabolite repression (CCR) mechanism, interconnecting regulatory system of the central metabolic pathways that regulate cell metabolism based on nutrient availability in the industrial yeasts. The regulatory proteins and their functions in the CCR signalling pathways in both yeasts are presented and discussed. We highlight the importance of metabolic signalling networks by signifying ways on how effective engineering strategies can be designed for generating novel regulatory circuits, furthermore to activate pathways that reconfigure the network architecture. We summarize the evidence that engineering of multilayer regulation is needed for directed evolution of the cellular network by putting the transcriptional control into a new perspective for the regulation of central carbon metabolism of the industrial yeasts; furthermore, we suggest research directions that may help to enhance production of recombinant products in the widely used, creatively engineered, but relatively less studiedP. pastoristhrough de novo metabolic engineering strategies based on the discovery of components of signalling pathways in CCR metabolism.