Gene therapy by aerosol is an attractive approach for the treatment of cystic fibrosis (CF). Clinical trials with aerosols in CF patients have been conducted by five different groups, three using adenoviral vectors and two using cationic liposomes carrying the coding sequence for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). These trials revealed that gene transfer from the lumen to the respiratory epithelium can currently be achieved in vivo, but only with low efficiency and for limited duration. Some of the many hurdles on the way to successful gene therapy for this disease will be discussed in this review. Innovative strategies need to be developed to reach this tantalizing goal.