There is considerable evidence that oxidative stress and a loss of nitric oxide bioactivity are key mediators of the vasculopathies associated with sickle cell disease. A comprehensive nutraceutical strategy for mitigating the contribution of oxidative stress to pathogenesis - dubbed "full-spectrum antioxidant therapy" - may have utility in this syndrome. This strategy entails concurrent administration of phycocyanobilin - a phytochemical richly supplied by spirulina, shown to inhibit NADPH oxidase in a manner analogous to its chemical relatives biliverdin and bilirubin; high-dose folate - recently shown to quench peroxynitrite-derived radicals and restore coupling of NO synthase; N-acetylcysteine - for boosting intracellular glutathione levels; and a phase 2 inducer such as lipoic acid - to further promote glutathione synthesis while increasing expression of antioxidant enzymes. Suboptimal endothelial arginine levels, reflecting increased plasma arginase activity and elevated ADMA, contribute to the loss of NO bioactivity in sickle cell disease; supplementation with the arginine precursor citrulline may ameliorate this defect. Increased intakes of plant-derived nitrate have the potential to diminish the quenching of NO by plasma hemoglobin in sickle cell patients, while boosting systemic NO production independent of NO synthase activity. In addition to the well-documented utility of hydroxyurea - possibly a suboptimal strategy for life-long therapy owing to its mutagenic activity - rational pharmaceutical options for managing sickle cell disease include pentoxifylline and phosphodiesterase 5 inhibitors such as sildenafil.