A decade ago it was widely anticipated that cystic fibrosis would be one of the first diseases to be treated by gene therapy. The difficult hurdle of cloning the responsible gene had been accomplished, its function was established and the lung appeared readily accessible for gene replacement. Since the first clinical trials for cystic fibrosis lung disease in the early 1990s it has become increasingly apparent that successful lung-directed gene therapy is significantly more complex than was first envisioned. Numerous obstacles including vector toxicity, inefficient transgene expression and limited vector production have delayed progress. An increased understanding of vector biology and host interaction has led to the development of novel strategies to enhance the efficiency and selectivity of gene delivery to the lung. Although significant challenges remain, there is now a realistic prospect of a clinically effective treatment in the next 10 years.