The metabolism of a xenobiotic is an important stage resulting in its toxification (bioactivation) or detoxification. The most common reaction is the oxidation catalyzed by the cytochrome P450 (CYP) enzyme system. An alternate enzyme for chemical oxidation is the prostaglandin H synthase (PGHS) also known as cyclooxygenase (COX). The PGHS is the initial enzyme in arachidonate metabolism and formation of prostanoids such as prostaglandins (PG), prostacyclins, and thromboxanes. However, 25 years ago it was found that during the reduction of the endogenous substrate, hydroperoxy-endoperoxide (PGG2) to hydroxy-endoperoxide (PGH2), the PGHS enzyme is capable to "co-oxidize" chemicals. In this reaction, a broad spectrum of chemicals can serve as electron donors such as phenolic compounds, aromatic amines, and polycyclic aromatic hydrocarbons. In contrast to numerous CYP enzymes in liver, the PGI is an alternate enzyme for xenobiotic metabolism in extrahepatic tissues. In respect of tissue distribution, PGHS can play an essential role in the bioactivation of e.g. procarcinogenic chemicals in certain target tissues that possess low CYP monooxygenase activity. Two PGHS isozymes have been identified: PGHS-1 and PGHS-2, which have very similar kinetic properties, but differ in regard to expression and regulation. In recent studies it was shown that not only endogenous stimuli but also drugs and environmental chemicals can activate PGHS-2 expression. Therefore the PGHS enzymes provide two interesting aspects for pharmacology and toxicology: a) the co-oxidation of chemicals and b) the altered synthesis of prostanoids after exposure to certain xenobiotics which can be essential for their ultimate toxicity.