Multiple superior physiological characteristics are required to confer recombinant mammalian cells with high productivity of quality product. Chief among them are favorable metabolic characteristics that sustain prolonged growth stage delayed cell death in late stage while providing ample glycan precursors for glycoprotein synthesis. While major metabolic pathways for key cell culture nutrients have been known for decades, new discoveries continue to reveal the intricacies of their regulation. With the aid of transcriptome and flux analysis, we have identified a number of key nodes that control the distribution of fluxes of the key nutrients, glucose and glutamine. Cell engineering in some of these key nodes has been shown to reduce production of lactate, the key inhibitory metabolite.  Intriguingly, many cells switch from a lactate producing state to a lactate consuming state in a stationary phase of growth. Such a metabolic switch is often related to a high productivity of recombinant protein. To better understand the mechanism of such a switch we simulated the metabolic fluxes using a mathematical model that incorporates the communication between mitochondria and cytosol. We conclude that the switch between the lactate production and consumption rate is a delicate balance among many metabolites and cofactors. To engineer the cells to alter the metabolic switch behavior will require a new paradigm of metabolic engineering.