MiR-21 plays a critical role in the fibrogenic activation of pulmonary fibroblasts and the progression of lung fibrosis. This study demonstrates that miR-21 is significantly upregulated in the lungs of mice with bleomycin-induced fibrosis and in patients with idiopathic pulmonary fibrosis (IPF). The expression of miR-21 is primarily localized to myofibroblasts, which are key cells in the fibrotic process. Administration of miR-21 antisense probes reduces the severity of experimental lung fibrosis, indicating that miR-21 is a key mediator in the pathogenesis of lung fibrosis. TGF-β1, a central mediator of fibrotic diseases, enhances miR-21 expression in pulmonary fibroblasts, and miR-21 amplifies TGF-β1's pro-fibrogenic effects. A potential mechanism involves miR-21's regulation of Smad7, an inhibitory Smad that modulates TGF-β1 signaling. These findings suggest that miR-21 is a central mediator in lung fibrosis and highlight the potential of miRNA-based therapies for treating fibrotic diseases like IPF. The study also shows that miR-21 antisense probes can effectively reduce collagen deposition and fibroblast activation in bleomycin-induced lung fibrosis, indicating their therapeutic potential. Overall, miR-21 is a promising target for developing novel treatments for fibrotic lung diseases.MiR-21 plays a critical role in the fibrogenic activation of pulmonary fibroblasts and the progression of lung fibrosis. This study demonstrates that miR-21 is significantly upregulated in the lungs of mice with bleomycin-induced fibrosis and in patients with idiopathic pulmonary fibrosis (IPF). The expression of miR-21 is primarily localized to myofibroblasts, which are key cells in the fibrotic process. Administration of miR-21 antisense probes reduces the severity of experimental lung fibrosis, indicating that miR-21 is a key mediator in the pathogenesis of lung fibrosis. TGF-β1, a central mediator of fibrotic diseases, enhances miR-21 expression in pulmonary fibroblasts, and miR-21 amplifies TGF-β1's pro-fibrogenic effects. A potential mechanism involves miR-21's regulation of Smad7, an inhibitory Smad that modulates TGF-β1 signaling. These findings suggest that miR-21 is a central mediator in lung fibrosis and highlight the potential of miRNA-based therapies for treating fibrotic diseases like IPF. The study also shows that miR-21 antisense probes can effectively reduce collagen deposition and fibroblast activation in bleomycin-induced lung fibrosis, indicating their therapeutic potential. Overall, miR-21 is a promising target for developing novel treatments for fibrotic lung diseases.