Ubiquitination is a posttranslational modification that regulates a variety of cellular functions depending on timing, subcellular localization, and type of tagging, as well as modulators of ubiquitin binding leading to proteasomal or lysosomal degradation or nonproteolytic modifications. Ubiquitination plays an important role in the pathogenesis of acute lung injury (ALI) and other lung diseases with pathologies secondary to inflammation, mechanical ventilation, and decreased physical mobility. Particularly, ubiquitination has been shown to affect alveolar epithelial barrier function and alveolar edema clearance by targeting the Na,K-ATPase and epithelial Na+ channels upon lung injury. Notably, the proteasomal system also exhibits distinct functions in the extracellular space, which may contribute to the pathogenesis of ALI and other pulmonary diseases. Better understanding of these mechanisms may ultimately lead to novel therapeutic modalities by targeting elements of the ubiquitination pathway.