Cystic fibrosis (CF) is an autosomal recessive disease that results in damage to organs containing secretory epithelial cells, such as the lung, intestines, pancreas and liver. CF results from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which functions as a chloride channel in the apical membrane of secretory epithelial cells. In the lung, the loss of CFTR activity results in abnormal epithelial ion transport, including defective cyclic AMP-mediated chloride (Cl-) efflux and the hyper absorption of sodium ions. These defects in ion transport affect the osmotic flow of water across the epithelium and result in thickened airway secretions which are not properly cleared from the lung. Patients with CF suffer from chronic pathogenic infection of the lungs which in turn results in the formation of purulent mucus, chronic inflammation and fibrosis, which eventually cause a loss of lung function. One approach to treat CF is to replace the defective copy of the gene encoding for CFTR with a correct copy employing one of a number of possible gene therapy vectors. This review summarizes the most recent progress towards gene therapy for CF employing cationic lipid:pDNA complexes. The results of recent clinical trials conducted in the nasal epithelium of CF patients are presented, followed by a description of preclinical studies conducted in order to support trials of aerosolized lipid:pDNA complexes into the lungs of CF patients. A brief overview of the results of these aerosol trials is presented, followed by a discussion of the lessons learned from these studies. More specifically, the issues of efficacy and toxicity of cationic lipid:pDNA complexes in the setting of the CF lung are discussed and recent findings which are relevant to these limiting issues are introduced. Finally, studies which point to the possibility of improved formulations capable of overcoming some of the barriers identified for the current generation of cationic lipid:pDNA complexes are introduced.