Peroxynitrite is a cytotoxic oxidant formed in vivo from the diffusional-controlled reaction between nitric oxide and superoxide radicals. Increased peroxynitrite formation has been related to the pathogenesis of multiple diseases, thus underlining the importance of understanding the mechanisms of its detoxification. In nature, different enzymatic routes for peroxynitrite decomposition have evolved. Among them, peroxiredoxins catalytically reduce peroxynitrite in vitro; modulation of their expression affects peroxynitrite-mediated cytotoxicity, and their content changes in pathologic conditions associated with increased peroxynitrite formation in vivo, thus indicating a physiologic role of these enzymes in peroxynitrite reduction. Selenium-containing glutathione peroxidase also catalyzes peroxynitrite reduction, but its role in vivo is still a matter of debate. In selected cellular systems, heme proteins also play a role in peroxynitrite detoxification, such as its isomerization by oxyhemoglobin in red blood cells. Moreover, different pharmacologic approaches have been used to decrease the toxicity related to peroxynitrite formation. Manganese or iron porphyrins catalyze peroxynitrite decomposition, and their protective role in vivo has been confirmed in biologic systems. Glutathione peroxidase mimetics also rapidly reduce peroxynitrite, but their biologic role is less well established. Flavonoids, nitroxides, and tyrosine-containing peptides decreased peroxynitrite-mediated toxicity under different conditions, but their mechanism of action is indirect.