Diabetes is a leading cause of death and disability. In 2004, 3.4 million people worldwide died of symptoms relating to high blood sugar. Diabetic complications are caused by organ damage resulting from long-term exposure to high blood sugar, and include diseases such as heart failure, kidney failure, vision loss and neuropathy. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) is an important component of the intracellular antioxidant machinery and a target for treatment of diabetic complications. This article reviews the role of NFE2L2 in diabetic complications with a focus on diabetic nephropathy, cardiomyopathy, neuropathy and retinopathy. Activation of NFE2L2 protects against oxidative stress in vitro and in vivo, and represents an important target for prophylaxis and treatment of diabetic complications. NFE2L2 has potential clinical applications for diabetic patients in the near future.