The ongoing COVID-19 pandemic has produced serious turmoil world-wide . Lung injury causing acute respiratory distress syndrome seems to be a most dreaded complication occurring in â¼30% . Older patients with cardiovascular comorbidities and acute respiratory distress syndrome have an increased mortality . Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system seems to be pivotal . In this context, angiotensin-converting enzyme 2 (ACE2), an angiotensin-converting enzyme homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions . Thus, concern was raised that the use of renin-angiotensin system inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID-19 virus . However, current data have appeased such concerns because there has been no clinical evidence of a harmful effect of these agents as based on observational studies . However, properly designed future studies will be needed to further confirm or refute current evidence . Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, whereas, in the same context, specific bradykinin inhibitors may also negate bradykinin's harmful effects . Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies . These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.