Nrf2, once regarded as a potential key to unlock novel therapies in the cardiovascular and cancer fields, has now assumed the role of a double-edged sword: when properly regulated, it can reduce ROS and increase wound healing but carries the possibility of chemotherapy resistance and cardiomyopathy when overexpressed by exogenous manipulation through natural and synthetic compounds. This evidence concerns the gene NFE2L2 and cardiomyopathy.