Transforming growth factor-betas (TGF-beta) regulate a wide variety of cellular functions in normal development and are involved in both tissue homeostasis and disease pathogenesis. The regulation of the TGF-beta family of growth factors is unique because they are targeted to the extracellular matrix in a biologically inactive form. The release from pericellular matrices and the activation of TGF-beta are important mechanisms in several pathophysiologic conditions. Reactive oxygen species (ROS) can activate TGF-beta either directly or indirectly via the activation of proteases. In addition, TGF-beta itself induces ROS production as part of its signal-transduction pathway. The lung is a unique organ, because its structures act as boundaries between gaseous and aqueous phases, allowing the utilization of inhaled oxygen. However, this renders pulmonary tissues vulnerable to the toxic effects of inhaled air. The oxidant pathways are especially relevant in the lung, where TGF-beta is known to have a role in tissue repair and connective tissue turnover. In pulmonary fibrosis, TGF-beta activation is considered as a hallmark of disease progression. More recently, the oxidative effects of cigarette smoking have been found to activate TGF-beta in chronic obstructive pulmonary disease (COPD), a disease consisting of emphysema, airway fibrosis, and focal lung fibrosis.