Introduction: Respiratory viruses can directly or indirectly damage the pulmonary defense barrier, potentially contributing to acute respiratory distress syndrome (ARDS). Despite developments in the understanding of the pathogenesis of ARDS, the underlying pathophysiology still needs to be elucidated. Areas covered: The PubMed database was reviewed for relevant papers published up to 2021. This review summarizes the currently immunological and clinical studies to provide a systemic overview of the epithelial-endothelial barrier, given the recently published immunological profiles upon viral pneumonia, and the potentially detrimental contribution to respiratory function caused by damage to this barrier. Expert opinion: The biophysical structure of host pulmonary defense is intrinsically linked with the ability of alveolar epithelial and capillary endothelial cells, known as the epithelial-endothelial barrier, to respond to, and instruct the delicate immune system to protect the lungs from infections and injuries. Recently published immunological profiles upon viral infection, and its contributions to the damage of respiratory function, suggest a central role for the pulmonary epithelial and endothelial barrier in the pathogenesis of ARDS. We suggest a central role and common pathways by which the epithelial-endothelial barrier contributes to the pathogenesis of ARDS.