The pathology of fibrosis is characterized by loss of cellular homeostasis and excessive extracellular matrix deposition, leading to diminished physiologic reserve and progressive organ failure. Although fibrosis can affect several organ systems, we focus on fibrosis of the lungs which serve a metabolic function to exchange inhaled atmospheric oxygen for carbon dioxide released from the systemic circulation. This gas-exchange occurs in terminal, thin-walled airway structures known as alveoli. Along with these gases, alveoli are exposed to airborne toxicants and particulates that contribute to a unique oxidizing environment under which tissue homeostasis must be maintained. The NADPH oxidase (NOX) family of enzymes are a major source of reactive oxygen species (ROS) that function as signaling molecules but may also contribute to oxidative damage in the context of aging when antioxidant defenses wane. Such an oxidant-antioxidant imbalance is evident in the age-related lung disease, idiopathic pulmonary fibrosis (IPF). While many NOXs have been implicated in inflammatory and fibrotic diseases of the lung, we will focus specifically on NOX4 that has emerged as a canonical pro-fibrotic NOX homolog in mammals. We take an in-depth look at the implications of ROS signaling and stress responses within the alveolar microniche that activates transitional cell states that lead to impaired or defective repair responses. We offer a perspective on preclinical studies and the current clinical trials in fibrotic disorders and provide insights into new strategies for therapeutic interventions in IPF.