The nuclear factor, erythroid 2 like 2 (NFE2L2) is an important transcription factor that protects cells from oxidative stress (OS). NFE2L2 deficiency in the placentas is associated with pregnancy complications. Phosphorylation of the transcription factor NFE2L2 controls mRNA abundance of genes encoding antioxidant proteins and enzymes. NFE2L2 pathway contributes to the environmental resistance of cancers by enhancing the antioxidant capacity. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates the expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. NRF2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation.