Pyruvate kinase isoform M2 (PKM2) is a glycolytic enzyme that mediates the conversion of phosphoenolpyruvate (PEP) to pyruvate. It has been suggested that PKM2 may have additional enzymatic activities and localizes to the nucleus to regulate transcription. Here, the authors show that PKM2 can act as a kinase in the nucleus. They found that nuclear PKM2 affected the expression of many genes; one of its targets was Mek5 (also known as Map2k5), the expression of which was increased following an interaction of PKM2 with signal transducer and activator of transcription 3 (STAT3). Specifically, PKM2 was found to phosphorylate STAT3 on Tyr705, leading to STAT3 activation and increased DNA binding affinity. Importantly, the authors observed that dimeric PKM2 localizes to the nucleus and is the active protein kinase, whereas the tetramer is found in the cytoplasm and acts as a pyruvate kinase.