Reactive oxygen species (ROS) are key regulators of metabolic disease pathophysiology, arising from both enzymatic and nonenzymatic sources. Excessive generation of ROS under diseases such as obesity, diabetes mellitus, and metabolic syndrome deranges the redox balance and triggers cellular dysfunction. Enzymatically, ROS generation largely involves the function of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidase, and mitochondrial electron transport chain components. These systems become overactive during conditions of hyperglycemia and dyslipidemia, increasing oxidative stress and promoting insulin resistance, endothelial dysfunction, and chronic inflammation. In addition, uncoupled nitric oxide synthase and cytochrome P450 enzymes further enhance ROS under conditions of metabolic stress. Nonenzymatic processes, including auto-oxidation of glucose, advanced glycation end-product (AGE) formation, and lipid peroxidation, also play critical roles, particularly during prolonged metabolic derangements. These oxidative events undermine cellular integrity and transduction pathways needed for glucose and lipid metabolism. Dissection of the interaction between enzymatic and nonenzymatic ROS formation is crucial for the delineation of novel therapeutic strategy. Targeting individual oxidative pathways might be of potential to counteract the development and complications of metabolic disease by restoring cellular redox equilibrium and enhancing metabolic robustness.