In the past 40 years, the mean survival of patients with cystic fibrosis (CF) has increased from less than 1 year to 30 years. The identification of the gene mutated in CF in 1989 has already been followed by the first phase of somatic gene therapy in 1993. The target organ of somatic gene therapy is the respiratory epithelium, which is progressively damaged by the chronic infection and inflammation characteristic of the disease. Since in the future, more patients may benefit from somatic gene therapy, the understanding of the mechanisms leading to chronic infection and inflammation becomes increasingly important. In the future, current therapeutic measures to protect the respiratory epithelium from damage, such as intravenous antimicrobial treatment, will be improved by the additional delivery of new drugs to the bronchial tree by aerosol. Amiloride and recombinant human DNAse administered by this route have the potential to improve mucociliary clearance. Antibiotics as well as protease inhibitors delivered by aerosol should contribute to prevent damage by infection and inflammation in order to increase the probability of successful somatic gene therapy in this disease.