Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting > 70,000 individuals worldwide. Despite improvements in current therapies, most patients do not survive beyond their early 30s. After cloning of the cystic fibrosis transmembrane regulator (CFTR) gene, there was considerable clinical interest in the possible therapeutic delivery of CFTR genes directly to the lung. Several clinical studies have since demonstrated proof-of-principle for correction of the underlying chloride defect in CF patients using viral and non-viral vectors. Inefficient gene transfer and host-antigen-specific immune responses caused by replication-deficient viral vectors have elevated non-viral approaches to becoming the field's most promising therapeutic contenders. Among these non-viral gene therapy vectors are cationic liposome/plasmid DNA complexes and compacted DNA nanoparticles carrying the CFTR gene, which have shown promise for the treatment of CF in phase I clinical trials. However, the levels of CFTR expression achieved in the respiratory epithelium were too low and only of limited duration. Improved strategies for efficient and prolonged expression of the transgene are therefore necessary. This review outlines the current repertoire of available gene vectors and discusses novel strategies to enhance the efficiency and selectivity of gene transfer for gene delivery into the lung.