Atmospheric pollutants and cigarette smoke influence the human respiratory system and induce airway inflammation, injury, and pathogenesis. Activation of the NF-E2-related factor 2 (Nrf2) transcription factor and downstream antioxidant response element (ARE)-mediated transcriptions play a central role in protecting respiratory cells against reactive oxidative species (ROS) that are induced by airway toxins and inflammation. Recent studies have revealed that Nrf2 can also target and activate many genes involved in developmental programs such as cell proliferation, cell differentiation, cell death, and metabolism. Nrf2 is closely regulated by the interaction with kelch-like ECH-associated protein 1 (Keap1), while also directly interacts with a number of other proteins, including inflammatory factors, transcription factors, autophagy mediators, kinases, epigenetic modifiers, etc. It is believed that the multiple target genes and the complicated interacting network of Nrf2 account for the roles of Nrf2 in physiologies and pathogeneses. This chapter summarizes the molecular functions and protein interactions of Nrf2, as well as the roles of Nrf2 and the Nrf2-interacting network in respiratory inflammation and diseases, including acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), cystic fibrosis (CF), viral/bacterial infections, and lung cancers. Therapeutic applications that target Nrf2 and its interacting proteins in respiratory diseases are also reviewed.