The role of mitochondria in diabetic complications has been viewed as a source of excess superoxide production leading to cell dysfunction. However, with the lack of benefit of non-specific anti-oxidant approaches this view needs to be re-evaluated. With recent studies using real-time imaging of superoxide, metabolomics, flux studies, transcriptomics and proteomics a new appreciation for the role of mitochondria in the evolution of diabetic kidney disease has emerged. Ongoing studies to further unravel the time course and mechanisms that reduce mitochondrial function will be relevant to novel therapies that could have a major impact on diabetic kidney disease and other diabetic complications.