In the Simultaneous Saccharification and Fermentation (SSF) of natural polymers, in addition to regulating the intracellular enzymes for metabolizing the nutrients, the excretion and synthesis of extracellular depolymerases for the breakdown of the polymeric substrates must be regulated by the microbes accordingly. Through a case study of the growth of a recombinant Saccharomyces cerevisiae capable of excreting both a-amylase and glucoamylase on starch, we demonstrated that the interlinked population balance and cybernetic modeling framework developed previously, could be used to abstract and rationalize the response of the yeast in regulating these depolymerases. Our model, calibrated using the data from the literature (Ulgen et al., Process Biochem. 2002, 37, 1157-1168), showed that both a-amylase and glucoamylase are needed for efficient SSF. Specifically, by cleverly regulating the excretion of both depolymerases, yeast growth is relatively unaffected by different starches, a subtle point which could not have been elicited by existing methods.