Chronic pain affects millions of people and often causes major health problems. Accumulating evidence indicates that the production of reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, is increased in the nociceptive system during chronic inflammatory and neuropathic pain, and that ROS can act as specific signaling molecules in pain processing. Reduction of ROS levels by administration of scavengers or antioxidant compounds attenuated the nociceptive behavior in various animal models of chronic pain. However, the sources of increased ROS production during chronic pain and the role of ROS in pain processing are poorly understood. Current work revealed pain-relevant functions of the Nox family of NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. In particular, significant expression of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system has been discovered. Studies using knockout mice suggest that these Nox enzymes specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. Accordingly, targeting Nox1, Nox2, and Nox4 could be a novel strategy for the treatment of chronic pain. Currently selective inhibitors of Nox enzymes are being developed. Here, we introduce the distinct roles of Nox enzymes in pain processing, we summarize recent findings in the understanding of ROS-dependent signaling pathways in the nociceptive system, and we discuss potential analgesic properties of currently available Nox inhibitors.