question: Overwhelming responses are seen at preclinical and clinical levels to understand and combat coronavirus disease 2019 [COVID-19] pandemic that is caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]. Encouraging successes are achieved in view of diagnostic, therapeutic and preventive measures including vaccines development. In fact, structural information of SARS-CoV-2 and molecular steps that help this virus to target AECs are appreciably studied. Furthermore, the heterogeneous and complex nature of COVID-19 is extensively revealed at molecular, genetic, and epigenetic and microenvironment levels. In spite of these developments in COVID-19 pathogenesis, reasons behind the targeted infection by SARS-CoV-2 to AECs are poorly understood. In this mini-review, we highlight the roles of pH and temperature of airway surface liquid [ASL] as a key determining factor that may contribute towards enhanced targeted infection by SARS-CoV-2 leading to COVID-19.