There is growing evidence to suggest that oxidative stress has a significant role in the pathogenesis of MS. Therapies that reduce oxidative stress, as well as inflammation, are of increasing interest. Fumaric acid esters are known to activate anti-oxidative pathways, as well as modulate the inflammatory cascade. Several in vivo studies have shown that nuclear factor E2-related factor 2 (Nrf2) has a role in attenuating proinflammatory stimuli through the modulation of cytokine signaling and through its involvement in glutathione homeostasis. For example, in one animal study, Nrf2-deficient mice were found to have increased expression of proinflammatory mediators, including cyclooxygenase-2, interleukin (IL)-1b, IL-6 and tumour necrosis factor-a, compared with wild-type mice. Nrf2 is also established as the guardian of redox homeostasis and has been shown to be critical for attenuating oxidative stress. Under oxidative conditions, Nrf2 enters into and accumulates within the nucleus of cells and activates the expression of a battery of cytoprotective and detoxification genes. A number of in vitro and in vivo studies have consistently demonstrated the key role of the Nrf2 signaling pathway in protecting the CNS from oxidative stress-related damage. Currently, oral dimethyl fumarate is the only agent that appears to directly target Nrf2, which it does by inducing the cleavage of kelch-like erythroid cell-derived protein with "cap'n'collar" homology-associated protein 1 (Keap1) from Nrf2 in the cell cytoplasm. By cleaving this Keap1-Nrf2 complex, Nrf2 is free to cross the nuclear membrane and interact with other nuclear transcription factors to upregulate the antioxidant response element. Via this mechanism, dimethyl fumarate appears to have a distinct dual mechanism of action in attenuating oxidative stress as well as in reducing inflammatory response.