Oxidative stress resulting from toxic effects of reactive oxygen species (ROS) plays an important role in the pathogenesis of a variety of diseases and important biological processes. Toxic effects of these ROS, including the superoxide and hydroxyl radicals, and hydrogen peroxide can cause cellular damage by oxidizing nucleic acids, proteins, and membrane lipids. While the chemical reactions involved in the generation and detoxification of ROS have been studied in great detail, little is known about the cellular and molecular responses to oxidative stress in mammalian cells. This article discusses some of the major aspects of these molecular responses, including alterations in the gene expression of antioxidant enzymes, stress-response genes, and cytokines. The regulatory mechanisms that control this genetic response are highly complex, involving activation of transcription factors and signal transduction pathways. Further characterization of the mechanisms that regulate these molecular responses is essential for understanding the physiologic function of the responses and for the development of new therapeutic modalities to defend and/or adapt to oxidant injury.