Neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase (Nedd4-1 and Nedd4-2) is a member of the HECT E3 ubiquitin ligase family. It has been shown to mediate numerous pathophysiological processes, including the regulation of synaptic plasticity and Wnt-associated signaling, via promoting the ubiquitination of its substrates, such as cyclic adenosine monophosphate (cAMP)-response element binding protein regulated transcription coactivator 3 (CRTC3), alpha-amino-3-hydroxy-5-methyl-4-isoxazo-lepropionic acid receptor (AMPAR), and Dishevelled2 (Dvl2). In the respiratory system, both Nedd4-1 and Nedd4-2 are expressed in epithelial cells and functionally associated with lung cancer development and alveolar fluid regulation. Nedd4-1 mediates lung cancer migration, metastasis, or drug resistance mainly through inducing phosphate and tension homology deleted on chromsome ten (PTEN) degradation or promoting cathepsin B secretion. Unlike Nedd4-1, Nedd4-2 displays more complex effects in lung cancers. On one hand it suppresses lung cancer cell migration and metastasis, and on the other hand it has been shown to promote lung cancer survival via inducing general control nonrepressed 2 (GCN2) degradation. Another important function of Nedd4-2 is to regulate the activity of epithelial sodium channel (ENaC), a membrane channel which mediates the clearance of fluid from the alveolar space at birth or during pulmonary edema. Here, we make an outlined review for the expression and function of Nedd4-1 and Nedd4-2 in the respiratory system in hope of getting an in-depth insight into their roles in lung disorders.