Prostaglandin-H synthase (PHS) can oxidize many xenobiotics and carcinogens (chemicals) in vitro and has been suggested to serve as an alternative metabolic activation enzyme, particularly in tissues low in monooxygenase activity. This article briefly describes types of PHS-catalyzed xenobiotic oxidations and discusses its determinants in cells. Methods employed for studying the involvement of PHS in the bioactivation of chemicals are reviewed with special emphasis on a cell culture system derived from ram seminal vesicles which has been used in studies on the metabolism and the genotoxicity of diethylstilbestrol.