Oxidative stress is implicated in many diseases in a variety of different organ systems. While specific antioxidant genes are known to contribute to the regulation and breakdown of reactive free radicals, harnessing their power to combat oxidative stress remains elusive due to the need for a coordinated regiment of several antioxidant enzymes acting together to produce therapeutic effect. Many of these enzymes share a common promoter element, the Antioxidant Response Element (ARE). Chemical activators of the ARE have shown promise as therapeutic effectors due to their ability to upregulate coordinated expression of a panel of antioxidant genes, but this strategy is lacking in cases where long-term oxidative stress is present. Nrf2 is a transcription factor that drives antioxidant gene expression. We hypothesized that Nrf2 overexpression can be used as therapy by which antioxidant genes facilitate redox homeostasis. Due to its safety profile, low immunogenicity, and ability to facilitate long term gene expression, Adeno-associated virus (AAV) was used to deliver persistent Nrf2 overexpression in mice. In this dissertation, I describe two studies in which we applied this Nrf2-based gene therapy strategy to rescue mouse models from oxidative stress-induced disease. First, AAV-Nrf2 was delivered systemically via tail vein injection to mediate Nrf2 overexpression primarily in the liver. AAV-Nrf2 gene replacement in Nrf2-/- mice, as well as overexpression in wild-type mice, was able to prevent mortality from acetaminophen-induced hepatotoxicity. Secondary outcomes of liver enzymes and liver histopathology were also characterized. Secondly, AAV-Nrf2 was injected intravitreally to mediate Nrf2 expression in the retina. AAV-Nrf2 overexpression successfully rescued mice from light-induced retinal degeneration, a model that recapitulates many features of age-related macular degeneration in humans. Outcome measures included retinal thickness measured using in vivo optical coherence tomography imaging and retinal function as measured by electroretinography. This work demonstrates that AAV-Nrf2 has viable therapeutic potential to combat oxidative stress across multiple organ systems. The long term persistence of rescue, along with the time course of loss and regaining of function following insult seen in the retinal model in particular, supports a potential role for Nrf2 in regeneration and tissue repair in addition to its role in combating acute oxidative insults.