The flavonoids are a diverse class of plant-derived polyphenols that have intriguing antioxidant activities, but they are not generally available in pure or inexpensive forms making them attractive opportunities for microbial biosynthesis. Because flavonoids are built around a common phenylbenzo-pyrone nucleus derived from phenyalanine and malonyl CoA, their synthesis in microorganisms represents a severe drain on both proteins and lipids needed for cell survival. At the same time, other endogenous pathways are competing for the flow of carbon within the host cell leading to reduction in the yield of flavonoid. To increase product yield, a systems biology approach will be presented, based on a comprehensive stoichiometric mathematical model of all of the known reactions and enzymes in E. coli, and the implementation of the genetic algorithm in order to select those pathways whose elimination enhances carbon flow into the flavonoid biosynthetic pathway while preserving the cell’s ability to grow. Grafting metabolic pathways from heterologous sources, together with targeted overexressions of E. coli native enzymes, a recombinant strain was developed with more than 1600-fold increase in the amount of flavanones (the common precursors of the vast majority of flavonoid molecules) compared to a control recombinant strain.