Reperfusion therapy following an acute myocardial infarction can detrimentally increase oxidative stress and cause myocyte death. This study showed that these side effects are mediated by troponin I-interacting kinase (TNNI3K); a myocyte-specific kinase. The authors developed two TNNI3K inhibitors that reduced mitochondria-derived superoxide generation and infarct size when given during reperfusion therapy in a mouse model. Moreover, the inhibitors preserved cardiac function and limited chronic adverse remodelling, which suggests that TNNI3K is a plausible target for heart disease therapy.