Acute respiratory distress syndrome (ARDS) is a severe condition characterized by bilateral lung opacities and refractory hypoxemia due to noncardiogenic pulmonary edema. Despite advances in understanding ARDS, its mortality remains high, and effective targeted therapies are lacking. The outbreak of COVID-19 has further increased ARDS mortality. Understanding ARDS pathophysiology and molecular mechanisms is crucial for developing effective treatments. This review summarizes ARDS pathogenesis, molecular mechanisms, and potential therapeutic strategies. ARDS involves dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance, and oxidative stress. Key signaling pathways include pattern recognition receptors (PRRs), NF-κB, Notch, JAK/STAT, MAPK, PI3K/AKT, ER stress, TGF-β, and TNF-α. These pathways regulate inflammation, alveolar-capillary permeability, and oxidative stress. Therapeutic strategies include pharmacologic agents, microRNA-based therapies, and mesenchymal stromal cell therapies. Understanding these pathways provides insights into ARDS development and potential therapeutic targets. Targeting these pathways may reduce ARDS mortality and improve outcomes.Acute respiratory distress syndrome (ARDS) is a severe condition characterized by bilateral lung opacities and refractory hypoxemia due to noncardiogenic pulmonary edema. Despite advances in understanding ARDS, its mortality remains high, and effective targeted therapies are lacking. The outbreak of COVID-19 has further increased ARDS mortality. Understanding ARDS pathophysiology and molecular mechanisms is crucial for developing effective treatments. This review summarizes ARDS pathogenesis, molecular mechanisms, and potential therapeutic strategies. ARDS involves dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance, and oxidative stress. Key signaling pathways include pattern recognition receptors (PRRs), NF-κB, Notch, JAK/STAT, MAPK, PI3K/AKT, ER stress, TGF-β, and TNF-α. These pathways regulate inflammation, alveolar-capillary permeability, and oxidative stress. Therapeutic strategies include pharmacologic agents, microRNA-based therapies, and mesenchymal stromal cell therapies. Understanding these pathways provides insights into ARDS development and potential therapeutic targets. Targeting these pathways may reduce ARDS mortality and improve outcomes.