The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, the Hubei region of China, has become a pandemic worldwide. It can transmit through droplets and enter via oral, nasal, and eye mucous membranes. It consists of single-stranded RNA (positive-sense), nonstructural proteins including enzymes and transcriptional proteins, and structural proteins such as Spike, Membrane, Envelope, and Nucleocapsid -proteins. SARS-CoV-2 mediates S-proteins entry and exit via binding to host cell surface proteins like tetraspanins. The transmembrane tetraspanins, CD151, CD9, and tetraspanin 8 (TSPAN8), facilitate the entry of novel coronaviruses by scaffolding host cell receptors and proteases. Also, CD151 was reported to increase airway hyperresponsiveness to calcium and nuclear viral export signaling. They may facilitate entry and exit by activating the serine proteases required to prime S-proteins in tetraspanin-enriched microdomains (TEMs). This article updates recent advances in structural proteins, their epitopes and putative receptors, and their regulation by proteases associated with TEMs. This review furnishes recent updates on the role of CD151 in the pathophysiology of SARS-CoV-2. We describe the role of CD151 in a possible mechanism of entry and exit in the airway, a major site for infection of SARS-CoV-2. We also updated current knowledge on the role of CD9 and TSPAN 8 in the entry and exit mechanism of coronaviruses. Finally, we discussed the importance of some small molecules which target CD151 as possible targeted therapeutics for COVID-19. In conclusion, this study could identify new targets and specific therapeutics to control emerging virus infections.