Neurodegenerative diseases are characterized by the loss of homeostatic functions that control redox and energy metabolism, neuroinflammation, and proteostasis. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master controller of these functions, and its overall activity is compromised during aging and in these diseases. However, NRF2 can be activated pharmacologically and is now being considered a common therapeutic target. Many gaps still exist in our knowledge of the specific role that NRF2 plays in specialized brain cell functions or how these cells respond to the hallmarks of these diseases. This review discusses the relevance of NRF2 to several hallmark features of neurodegenerative diseases and the current status of pharmacological activators that might pass through the blood-brain barrier and provide a disease-modifying effect.