Cystic fibrosis(CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator(CFTR) gene that encodes a cAMP-regulated anion channel.Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation.Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities.A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation.After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990.In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia.Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF.Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs.While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality.