Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in cellular defense against toxic and oxidative insults by regulating genes involved in antioxidant responses and drug detoxification. NRF2 activation enhances cellular resistance to chemical carcinogens and inflammatory challenges. Beyond its antioxidant functions, NRF2 is involved in various cellular processes, including metabolism, inflammation, and immune response. Its activity is tightly regulated through a complex network of transcriptional and post-translational mechanisms, which enable it to orchestrate cellular responses and adaptations to various pathological stressors. Elevated or decreased NRF2 activity is associated with many metabolism- and inflammation-related diseases. Recent studies have identified new NRF2 target genes and functions, highlighting its pleiotropic nature. This review summarizes the regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in cellular defense against toxic and oxidative insults by regulating genes involved in antioxidant responses and drug detoxification. NRF2 activation enhances cellular resistance to chemical carcinogens and inflammatory challenges. Beyond its antioxidant functions, NRF2 is involved in various cellular processes, including metabolism, inflammation, and immune response. Its activity is tightly regulated through a complex network of transcriptional and post-translational mechanisms, which enable it to orchestrate cellular responses and adaptations to various pathological stressors. Elevated or decreased NRF2 activity is associated with many metabolism- and inflammation-related diseases. Recent studies have identified new NRF2 target genes and functions, highlighting its pleiotropic nature. This review summarizes the regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.