Hypoxia during sleep and exercise may occur in an important number of patients with cystic fibrosis (CF). Despite its recognition, no clear definition for hypoxia in CF exists, and nor do guidelines for commencing oxygen therapy. CF patients with hypoxia may have increased pulmonary artery pressure, reduced exercise ability, and skeletal muscle strength, and most importantly of all worse sleep quality, and a worse quality of life. Laboratory and rodent evidence exists to suggest that hypoxia may contribute to the decline in lung function in CF by upregulating lung inflammation, and encouraging growth of Pseudomonas aeruginosa, the most important pathogen associated with CF lung disease. The effects of hypoxia in childhood CF need to be fully studied, and a potential expanded role for oxygen as therapy in CF may be worthy of exploration.