Acute Respiratory Distress Syndrome (ARDS) is a critical condition characterized by bilateral chest radiographical opacities and refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advancements, ARDS remains a high-mortality disease with limited effective pharmacotherapeutic agents. The outbreak of COVID-19 has further increased the mortality rate of ARDS. Understanding the pathophysiology and molecular mechanisms of ARDS is crucial for developing effective therapeutic strategies. This review provides a comprehensive overview of ARDS, covering its pathophysiology, molecular mechanisms, and potential therapeutic targets. The pathophysiology of ARDS involves dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance, and oxidative stress. Inflammation is initiated by pattern recognition receptors (PRRs) in innate immune cells, leading to the release of inflammatory cytokines and chemokines. Neutrophils and adaptive immune cells contribute to the inflammatory injury and thrombosis. The alveolar-capillary barrier dysfunction is characterized by increased permeability of the lung endothelium and alveolar epithelium, leading to edema formation. Impaired alveolar fluid clearance results in persistent alveolar edema, hypoxemia, and hypercapnia. Oxidative stress, caused by reactive oxygen species (ROS), exacerbates lung injury and inflammation. The review discusses the molecular mechanisms and signaling pathways involved in ARDS, including the NF-κB, Notch, JAK/STAT, MAPK, PI3K/AKT, ER stress, TGF-β/Smad, and TNF-α signaling pathways. These pathways play crucial roles in inflammation, cell death, and barrier dysfunction. Targeting these pathways may offer potential therapeutic strategies for ARDS. Emerging evidence suggests that different forms of cell death, such as necrosis, apoptosis, necroptosis, ferroptosis, and pyroptosis, coexist in the endothelium and epithelium of the lung during ARDS, leading to barrier dysfunction and pulmonary edema. Apoptosis, induced by extrinsic or intrinsic pathways, and necroptosis, initiated by various receptors and inflammatory cytokines, are particularly significant in ARDS pathogenesis. Overall, this review highlights the complex pathophysiology of ARDS and provides insights into potential therapeutic targets, including pharmacologic therapies, microRNA-based therapies, and mesenchymal stromal cell therapies.Acute Respiratory Distress Syndrome (ARDS) is a critical condition characterized by bilateral chest radiographical opacities and refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advancements, ARDS remains a high-mortality disease with limited effective pharmacotherapeutic agents. The outbreak of COVID-19 has further increased the mortality rate of ARDS. Understanding the pathophysiology and molecular mechanisms of ARDS is crucial for developing effective therapeutic strategies. This review provides a comprehensive overview of ARDS, covering its pathophysiology, molecular mechanisms, and potential therapeutic targets. The pathophysiology of ARDS involves dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance, and oxidative stress. Inflammation is initiated by pattern recognition receptors (PRRs) in innate immune cells, leading to the release of inflammatory cytokines and chemokines. Neutrophils and adaptive immune cells contribute to the inflammatory injury and thrombosis. The alveolar-capillary barrier dysfunction is characterized by increased permeability of the lung endothelium and alveolar epithelium, leading to edema formation. Impaired alveolar fluid clearance results in persistent alveolar edema, hypoxemia, and hypercapnia. Oxidative stress, caused by reactive oxygen species (ROS), exacerbates lung injury and inflammation. The review discusses the molecular mechanisms and signaling pathways involved in ARDS, including the NF-κB, Notch, JAK/STAT, MAPK, PI3K/AKT, ER stress, TGF-β/Smad, and TNF-α signaling pathways. These pathways play crucial roles in inflammation, cell death, and barrier dysfunction. Targeting these pathways may offer potential therapeutic strategies for ARDS. Emerging evidence suggests that different forms of cell death, such as necrosis, apoptosis, necroptosis, ferroptosis, and pyroptosis, coexist in the endothelium and epithelium of the lung during ARDS, leading to barrier dysfunction and pulmonary edema. Apoptosis, induced by extrinsic or intrinsic pathways, and necroptosis, initiated by various receptors and inflammatory cytokines, are particularly significant in ARDS pathogenesis. Overall, this review highlights the complex pathophysiology of ARDS and provides insights into potential therapeutic targets, including pharmacologic therapies, microRNA-based therapies, and mesenchymal stromal cell therapies.