AbstractCancer cells exhibit high rates of glycolysis and glutaminolysis. Glycolysis can provide energy and glutaminolysis can provide carbon for anaplerosis and reductive carboxylation to citrate. However, all these metabolic requirements could be in principle satisfied from glucose. Here we investigate why cancer cells do not satisfy their metabolic demands using aerobic biosynthesis from glucose. Based on the typical composition of a mammalian cell we quantify the energy demand and the OxPhos burden of cell biosynthesis from glucose. Our calculation demonstrates that aerobic growth from glucose is feasible up to a minimum doubling time that is proportional to the OxPhos burden and inversely proportional to the mitochondria OxPhos capacity. To grow faster cancer cells must activate aerobic glycolysis for energy generation and uncouple NADH generation from biosynthesis. To uncouple biosynthesis from NADH generation cancer cells can synthesize lipids from carbon sources that do not produce NADH in their catabolism, including acetate and the amino acids glutamate, glutamine, phenylalanine and tyrosine. Finally, we show that cancer cell lines have an OxPhos capacity that is insufficient to support aerobic biosynthesis from glucose. We conclude that selection for high rate of biosynthesis implies a selection for aerobic glycolysis and uncoupling biosynthesis from NADH generation.