Cystic fibrosis (CF) represents the most common lethal autosomal recessive disorder in the Caucasian population. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in abnormal Na(+) and Cl(-) transport in several tissues. Its main clinical manifestations include bronchopulmonary infections along with gastrointestinal and nutritional disorders. Intense and recurrent inflammation ultimately leads to an overabundance of activated neutrophils and macrophages that contribute to free radical generation. Furthermore, CFTR defects directly affect glutathione transport and homeostasis, while intestinal fat malabsorption limits uptake of endogenous antioxidant vitamins. Collectively, these abnormal events disturb the balance between pro- and anti-oxidants and promote oxidative stress, which may play a significant role in CF-related diabetes (CFRD), a severe complication associated with a drastic increase of morbidity and mortality. This review will focus on the involvement of oxidative stress in CF pathology, especially its role in the occurrence of CFRD. The multiple abnormalities in the oxidant/antioxidant balance could be a potential target for a new therapeutic approach.