The Drosophila melanogaster tracheal system and the mammalian lung are branching networks of tubular epithelia that convert during late embryogenesis from liquid- to air-filling. Little is known about how respiratory-tube size and physiology are coordinated. Here, we show that the Drosophila wurst gene encodes a unique J-domain transmembrane protein highly conserved in metazoa. In wurst mutants, respiratory-tube length is increased and lumen clearance is abolished, preventing gas filling of the airways. Wurst is essential for clathrin-mediated endocytosis, which is required for size determination and lumen clearance of the airways. wurst recruits heat shock cognate protein 70-4 and clathrin to the apical membrane of epithelial cells. The sequence conservation of the single Wurst orthologues in mice and humans offer new opportunities for genetic studies of clinically relevant lung syndromes caused by the failure of liquid clearance and respiratory-tube size control.