NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that binds to the promoter sequence "antioxidant responsive element (ARE)" leading to coordinated up-regulation of ARE-driven detoxification and antioxidant genes. Since the expression of a wide array of antioxidant and detoxification genes are positively regulated by the ARE sequence, Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress. In support of this, numerous studies have shown that Nrf2 protects many cell types and organ systems from a broad spectrum of toxic insults and disease pathogenesis. This Nrf2-conferred, multi-organ protection phenomenon raises an interesting question about how a single protein can protect many different organs from various toxic insults. A possible molecular mechanism explaining this phenomenon is that Nrf2 protects many different cell types by coordinately up-regulating classic ARE-driven genes as well as cell type-specific target genes that are required for the defense system of each cell type in its unique environment. This hypothesis is supported by microarray data indicating the protective role of Nrf2 is conveyed through both known ARE-driven genes and novel cell type-specific genes. The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.