Since the discovery of the CF transmembrane receptor (CFTR) gene in 1987, CF has been considered the major lung disease for intervention through gene therapy. To date, > 10 clinical trials have been reported without showing a convincing restoration of function.19 Several reasons can be considered for this failure. (1) The ideal vector system has not yet been developed. Adenoviral vectors, AAV, and liposomes have been shown to transfer sufficient amounts of gene to the lung, but expression is always transient and the levels of expression are never high enough or lasting.5,7,19 The problems associated with repeat administration are yet unsolved, as has been mentioned. It has been shown that a third dose of adeno-CFTR administered 3 months after the first did not result in any further gene expression. A trial7 investigating the repeat administration of AAV-CFTR is currently underway. (2) The answers to the questions of which pulmonary region and which cells are the best target for CF gene therapy still must be elucidated. Clinical observations19 have shown that CF is initially localized in small airways, which are likely not within reach by the aerosols currently in use. Mucous plugs and local infections may be real obstacles for gene transfer. The main target tissue for gene transfer is the superficial epithelium, which exhibits all ion transport functions of CFTR and is best accessible via the topical administration of vectors. However, the constitutively highest level of CFTR gene expression is localized in bronchial submucosal gland cells. These glands may be better accessed by the vasculature and systemic vector application.5,19 Another attempt to deliver gene vectors to these cells is to use adjuncts that can open tight junctions between surface epithelial cells (eg, sodium caprate).,7 (3) The replacement of the CFTR gene in the airways alone will probably not compensate for all functional defects in CF patients. Data from the past few years20have also suggested an impaired ability to clear bacterial airway infections, partly due to malfunctioning antimicrobial peptides (eg, human β-defensin 1). Gene transfer could be used to deliver cytokines to the lung as an adjuvant therapy and thereby support the host response against bacteria. In pneumonia models, the survival of animals was improved by transient transgene expression of interleukin (IL)-12 and interferon (IFN)-γ, resulting in enhanced clearance of Klebsiella pneumoniae and Pseudomonas aeruginosa.21 This fact has important clinical relevance because of the increasing antibiotic resistance of P aeruginosa, which persistently colonizes airways in almost all CF patients.