The mammalian lung and the Drosophila airways are composed of an intricate network of epithelial tubes that transports fluids or gases and converts during late embryogenesis from liquid- to air-filling. Conserved growth factor pathways have been characterized in model organisms such as Drosophila or the mouse that control patterning and branching of tubular networks. In contrast, knowledge of the coordination of respiratory tube size and physiology is still limited. Latest studies have shown that endocytosis plays a major role in size determination and liquid clearance of the respiratory tubes and a new key regulator of these processes was identified, the Drosophila Wurst protein. wurst encodes a J-domain transmembrane protein which is essential for Clathrin-mediated endocytosis. It is evolutionary conserved and single Wurst orthologs are found in mammals (termed DNAJC22). In this commentary, we discuss the role of Wurst/DNAJC22 and address whether these proteins may be general regulators of Clathrin-mediated endocytosis.