Per recent studies, state that COVID-19 actually enters the cells through membrane fusion. This is the reason why studies are focused on the use of human angiotensin-converting enzyme 2 (ACE2) as a cell receptor and its spike (S) protein as they mediate membrane fusion activity. The evolved, high level of activity to mediate cell to cell fusion has resulted in an enhanced fusion capacity. Inhibition of COVID-19 infection targets the spike proteins that harbor the capacity for membrane mediated fusion. Vaccinations are based on the mediation of spike (S) glycoprotein mediating the fusion of the virus and its host cell membranes. The fusion mechanism is also studied as a potential target for antiviral development.