Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular defense, orchestrating a complex network of antioxidant and detoxification responses. Traditionally, its activity was attributed to Keap1-mediated degradation and cysteine sensing, but it is now understood to be influenced by various other factors. These include phosphorylation by different kinases, interactions with diverse protein partners, and epigenetic modifications. This multifaceted regulation highlights the complexity of Nrf2's role in maintaining cellular homeostasis and its involvement in various diseases, necessitating further investigation to fully uncover its intricate control mechanisms.