All aerobic organisms are exposed to oxidative stress during their lifetime and are required to respond appropriately for maintenance of their survival and homeostasis. Sustained exposure to oxidative stress has devastating effects in organisms, and, not surprisingly, oxidative stress has been implicated in numerous human diseases. Therefore, an understanding of how mammals respond to oxidative stress is crucial both biologically and clinically. Intracellular signaling pathways, which are activated in response to excessive oxygen radicals, play essential roles in overcoming oxidative stress. The mitogen-activated protein kinase (MAPK) signaling pathways are involved in diverse physiological processes, and are critical for induction of oxidative stress responses. In this review, we will discuss the physiological roles of MAPKs in oxidative stress, the upstream signaling pathways leading to MAPK activation, their regulation, and the MAPK downstream substrates, with a focus on mammalian systems.