Nrf2 is a pleiotropic master transcription factor, which responds to diverse oxidative and electrophilic environmental stresses that circumvent Nrf2's repression and proteasomal degradation by its repressor, Keap1 by oxidation of Keap1. Nrf2 then translocates to the nucleus, and activates a cytoprotective gene pathway network of over 2000 genes. Nrf2 activated responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, asthma, sepsis and emphysema as discussed here, both in murine models and human patients. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing to reduce ER stress and consequent cell death, both involved in lung injury. Furthermore, Nrf2 activators, such as Sulforaphane (a natural supplement from broccoli extract) are demonstrated as supplementary drugs in COPD prevention and treatment along with the highly prescribed, anti-inflammatory glucocorticoids. Nrf2 activation by Sulforaphane accentuates the efficacy of glucocorticoids in COPD patients by decreasing nitrosative stess associated inflammation.