Acute cardiac hypoxia produces life-threatening elevations in late sodium current (I(LATE)) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of Na(V)1.5 channels so they reopen when normally inactive, late in the action potential. Na(V)1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in I(LATE), a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced I(LATE) is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients.