Non-viral methods of gene transfer are being investigated to treat cystic fibrosis (CF) and include naked DNA, lipid-DNA complexes and complexes of DNA with polycations such as poly-L-lysine (poly K) or polyethylenimine (PEI), all of which can carry the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most recent promising strategy is the use of polycation-DNA complexes, particularly those prepared with poly-K and substituted with polyethylene glycol. These complexes produced partial correction of the CF defect in a mouse model with minimal toxicity, and have advanced to clinical trial. Improvements in this and other non-viral methods are in process and include i). targeting the complexes to the desired cells using receptor ligands, ii). lessening toxicity by changing the mix of lipids or adding protective molecules to polycations, iii). modifying the plasmid DNA to reduce inflammatory CpG sequences and enhance intensity, duration and tissue specificity of expression, and iv). modification of the complexes to improve nuclear access.