The M2 isoform of pyruvate kinase, the final rate-limiting enzyme of aerobic glycolysis, is expressed during embryonic development, whereas the M1 isoform is expressed in differentiated cells due to alternative splicing. By utilizing murine embryonic stem cells (ESCs) , Konno et al showed that the Pkm2 allele plays an important role in establishing intracellular redox conditions and modulating oxidative phosphorylation events to achieve an appropriate ESC differentiation program.