Gene transfer to the tracheobronchial tree has been an active area of investigation since the discovery of the genetic defect in the cystic fibrosis transmembrane conductance regulator over two decades ago. Cystic fibrosis (CF) is the most common lethal monogeneic disorder for which there is no cure short of lung transplantation. The ultimate goal of gene therapy in CF is to achieve efficient gene transfer at a level and distribution in target tracheobronchial epithelial cells and submucosal gland cells, which results in the genotypic and phenotypic correction of CF. This article reviews the current challenges and limitations of postnatal gene therapy to the tracheobronchial tree, and the potential advantages of fetal gene therapy for CF. We review recent work with novel viral vectors to achieve extremely efficient gene transfer in target cells in the respiratory epithelium and submucosal glands in models that are representative of the developing human fetal trachea. Finally, we will examine the prospects for, limitations of, and regulatory challenges facing the translation of fetal gene therapy from research to clinical application.