Prostaglandin (PG)E₂ is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein–coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE₂ has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE₂ to limit many of the pathobiologic features of lung fibroblasts and myofibroblasts, including the ability of PGE₂ to limit fibroblast proliferation, migration, collagen secretion, and, as originally reported in the Journal by us in 2003, the ability to limit transforming growth factor (TGF)-β–induced myofibroblast differentiation. In the setting of lung fibrosis, PGE₂ production and signaling is often diminished. In the last 8 years, significant advances have been made to better understand the dysregulation of PGE₂ production and signaling in the setting of lung fibrosis. We also have a clearer picture of how PGE₂ inhibits myofibroblast differentiation and the receptor signaling pathways that can influence fibroblast proliferation. This review highlights these recent advances and offers new insights into the potential ways that PGE₂ and its downstream signals can be regulated for therapeutic benefit in a disease that has no validated treatment options.