We propose that (a) the imbalance in the action of ACE- and ACE2-derived peptides, i.e., the increased ANGII versus ANG(1–7) ratio, which occurs due to SARS-CoV-2 binding-mediated diminishment of ACE2 expression, along with, (b) the high ACE-2 expression levels-related increased tropism of the virus to vital human organs (e.g., kidneys and heart) are major drivers of COVID-19 pathobiology. This evidence concerns the gene ACE2 and COVID-19.