Ozone (O3) is a secondary atmospheric pollutant that causes widespread damage to vegetation, including cotton. The high temperatures and abundant sunlight that lead to good cotton yields also lead to production of O3. The early crop loss experiments of the 1970s identified upland cotton as particularly sensitive to O3. Exposure to ambient concentrations of O3 resulted in a 10 to >15% loss in economic yield. More recent experiments with modern cultivars have confirmed damage to upland and Pima cultivars but have not assessed yield loss under agronomic conditions. It is likely that selection for yield in high O3 environments has led to inadvertent selection for tolerance to O3. Ozone reduces yield and fiber quality, mediated by O3-induced changes in gross photosynthesis, respiration, and translocation of current photosynthate out of source leaves. Ozone typically reduces root development and the root-to-shoot biomass ratio, which has secondary effects on plant growth and development and on water relations. Ozone also reduces stomatal conductance as a primary defense against entry of O3 into the plant, but this also restricts entry of CO2 and therefore photosynthesis. Ozone is clearly phytotoxic and impacts cotton as well as other species. Recent research has led to understanding many aspects of the mechanism of O3 damage and could lead to targeted approaches to improving O3 tolerance, and therefore, yield in O3-impacted production areas.