NF-κB is a multifunctional redox sensitive transcription factor. In neurodegenerative disorders such as Alzheimer's, Huntington's, Parkinson's disease and amyotrophic lateral sclerosis (ALS), inducible NF-κB activation is observed in glial cells (astrocytes and microglia) as an inflammatory response that regulates the expression of cytokines, chemokines and adhesion molecules as well as the generation of reactive oxygen (ROS) and nitrogen species (RNS). As such, NF-κB activation is thought to contribute to neuronal loss. However, there is strong evidence demonstrating that in neurons, NF-κB protects against cell death progression by regulation of anti-apoptotic genes. Understanding the molecular pathways involved in NF-κB activation during neurodegeneration and its downstream signaling mediating pro-survival, pro-death and inflammatory responses will provide novel targets for therapeutic intervention. In this chapter we revise the role of NF-κB in neurodegeneration, its role in oxidative stress and antioxidant defense in the brain, and its regulation by redox homeostasis and oxidative stress.