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Science’s STKE focuses on the signaling pathways activated in response to pathological accumulation of reactive oxygen species (ROS), as well as on mechanisms by which cells have harnessed these reactive molecules as active participants in signaling that leads to a desirable cellular response. ROS are chemically reactive because they contain unpaired electrons and, depending on the location of their production and the molecules with which they interact, they can cause cellular damage or trigger specific signaling events. Indeed, kinases and phosphatases are now recognized as key molecules that can be modified by interaction with ROS, and the Protocol by Wu and Terada describes a method for detecting oxidatively modified protein tyrosine phosphatases. In a Perspective, Michel et al. discuss how susceptibility to elevated ROS contributes to death of specific neurons and in a Review, Storz discusses the signaling pathways activated to detoxify ROS and how mitochondrial ROS may contribute to aging.