Contraction-induced production of reactive oxygen species has been shown to cause oxidative stress to skeletal muscle. As an adaptive response, muscle antioxidant defense systems are upregulated in response to exercise. Nuclear factor κB and mitogen-activated protein kinase are two major oxidative-stress-sensitive signal transduction pathways that have been shown to activate the gene expression of a number of enzymes and proteins that play important roles in maintenance of intracellular oxidant–antioxidant homeostasis. This mini-review will discuss the main mechanisms and gene targets for these signaling pathways during exercise and the biological significance of the adaptation.