Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high-dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to "pinch hit" for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin-that boost cellular expression of antioxidant enzymes and glutathione-as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here.