Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory lung diseases that are characterized by systemic and chronic localized inflammation and oxidative stress. Sources of oxidative stress arise from the increased burden of inhaled oxidants, as well as elevated amounts of reactive oxygen species (ROS) released from inflammatory cells. Increased levels of ROS, either directly or via the formation of lipid peroxidation products, may play a role in enhancing the inflammatory response in both asthma and COPD. Moreover, in COPD it is now recognized as the main pathogenic factor for driving disease progression and increasing severity. ROS and lipid peroxidation products can influence the inflammatory response at many levels through its impact on signal transduction mechanisms, activation of redox-sensitive transcriptions factors, and chromatin regulation resulting in pro-inflammatory gene expression. It is this impact of ROS on chromatin regulation by reducing the activity of the transcriptional co-repressor, histone deacetylase-2 (HDAC-2), that leads to the poor efficacy of corticosteroids in COPD, severe asthma, and smoking asthmatics. Thus, the presence of oxidative stress has important consequences for the pathogenesis, severity, and treatment of asthma and COPD. However, for ROS to have such an impact, it must first overcome a variety of antioxidant defenses. It is likely, therefore, that a combination of antioxidants may be effective in the treatment of asthma and COPD. Various approaches to enhance the lung antioxidant screen and clinical trials of antioxidant compounds are discussed.