As we deal with the COVID-19 pandemic we face a controversy concerning its pathophysiology and how to integrate available knowledge into practice while awaiting study outcomes. COVID-19’s pathophysiology remains elusive, as reflected in putative mechanisms that remain unsupported by robust evidence. Some models draw on clinical observations without reference to supporting data from genomic, proteomic, molecular, physiological, and other data pertaining to human coronaviruses. Consequently, some proposed models for COVID-19 pathophysiology and their corresponding treatment options remain highly divergent. To provide a pathophysiological model that better describes the different phenotypic presentations of the disease in concordance with existing research on the renin-angiotensin system, previously described pathophysiological processes for other human coronavirus infections and the genomic similarities between the SARS and SARS-CoV-2 viruses, we developed a conceptual model,“epithelial-endothelial crosstalk at alveolar-capillary membrane” that we believe can help explain the pathogenesis of COVID-19.