Over thirty years ago, the observations that eventually led to the discovery of the NADPH oxidase were made by Baehner, Karnovsky, and colleagues (1–3). These have served as a focal point of interest in placing reactive oxygen species (ROS) in the conceptual forefront of the biomedical community. Over the last decade, the examination of the roles of oxygen and redox tone in regulating cell function has turned inward to the intracellular environment. Because oxidative metabolism is central to the biology and health of all humans, how we respond to conditions of low and high oxygen stress has become a critical consideration in biology and medicine. Humans live in a world where we continually balance the use of oxygen as a source of energy, and as a source of cellular injury. The generation of oxygen radicals secondary to mitochondrial disruption, the activation of cellular NADPH oxidases, the metabolism of xenobiotics, or other forms of oxidative stress can lead to mutations in DNA, lipid peroxidation, and protein damage. We have therefore evolved a marvelously complex system of both defense mechanisms and sensing mechanisms for changes in cellular redox tone. These include the enzymes superoxide dismutase, catalase, and glutathione peroxidase that detoxify ROS. We have also developed signaling mechanisms that utilize ROS to initiate processes that allow cells to survive exposure to oxidative stress within certain tolerances, but also, when stress and damage become too great, to ensure cell death. How these pathways are initiated and controlled on a molecular basis by ROS and also molecular oxygen is at the heart of what is generally considered redox signaling and the response to oxidative stress. The molecular species that fall under the term ROS include superoxide, hydrogen peroxide (H 2 O 2), hydroxyl radical, and singlet oxygen. Each of these can play a role in a variety of intracellular processes. Finally, we have adapted these molecular species, particularly H 2 O 2 and (NO), as signaling molecules in multiple biological processes.

The organization of redox signaling and the use of oxygen to transmit information are proving to be much more complex than one could have originally imagined. As this Perspective series evolved, discussions with the authors suggested that we should cast a wide net and include various mechanisms by which oxygen and reducing equivalents have been adapted to transmit information within cells, or to create cellular damage. Our discussions seemed to raise as many questions as they answered. In the resulting series, several broad areas emerge that may focus the thinking of readers in new directions.