Abstract When the levels of free radicals and another reactive species exceed the existing levels of antioxidants, a destructive phenomenon called oxidative stress arises. This occurs as a response to the increased generation of cellular reactive oxygen species (ROS) and cellular reactive nitrogen species (RNS) during endogenous metabolic processes in the context of protection mechanisms against infectious pathogens, or exogenously, from inhaled harmful gases or particles such as air contaminants, cigarette smoke, ozone, nitrogen dioxide, and several vocational dusts. At physiological circumstances, endogenous reactive species generation is controlled firmly, and cells are protected from the risks of free radicals by endogenous antioxidant. If this stable system becomes disturbed, it may provoke oxidant–antioxidant imbalances, which, in turn, stimulate the emergence of pathological reactions that cause a range of nonpulmonary and pulmonary diseases, especially chronic obstructive pulmonary disease (COPD). This chapter focuses on the effect of oxidative stress, as well as its types, sources, and relevance in the emergence and progression of COPD.