This review summarizes the mechanisms of SARS-CoV-2 entry into host cells, focusing on the structural and cellular processes involved. SARS-CoV-2, like SARS-CoV, uses the angiotensin-converting enzyme 2 (ACE2) as its primary receptor. The virus's spike (S) protein binds to ACE2 and undergoes conformational changes to facilitate membrane fusion. The S protein is cleaved by proteases such as furin and TMPRSS2, which are essential for the entry process. The cleavage of the S1–S2 boundary and the S2' site within the S2 subunit is critical for the virus to engage with the host cell and initiate fusion. The S protein is composed of two subunits, S1 and S2. S1 binds to ACE2, while S2 mediates membrane fusion. The S2 subunit contains a fusion peptide that is exposed after cleavage, allowing the virus to merge with the host cell membrane. The entry process involves two proteolytic cleavage steps: one at the S1–S2 boundary and another at the S2' site. The first cleavage occurs in the virus-producing cell, while the second occurs in the target cell. TMPRSS2, a transmembrane serine protease, is present at the cell surface and facilitates S protein activation at the plasma membrane. In contrast, cathepsin L, a lysosomal protease, mediates S2' cleavage in endosomes. The entry of SARS-CoV-2 can occur through two distinct pathways: one involving TMPRSS2 at the cell surface and another involving cathepsin L in endosomes. The S protein's structure and conformational changes are crucial for the entry process. The receptor-binding domain (RBD) of the S protein interacts with ACE2, and mutations in the RBD can affect binding affinity and viral entry. Neutralizing antibodies target the RBD and other regions of the S protein, highlighting the importance of these regions in viral entry. The review also discusses the role of ACE2 orthologues in reservoir species and the adaptations that facilitate human transmission. Additionally, it examines the potential of vaccines, antibodies, and other therapeutics targeting SARS-CoV-2 entry mechanisms. The study highlights the complex interplay between viral proteins, host receptors, and cellular processes that enable SARS-CoV-2 to infect and replicate in human cells.This review summarizes the mechanisms of SARS-CoV-2 entry into host cells, focusing on the structural and cellular processes involved. SARS-CoV-2, like SARS-CoV, uses the angiotensin-converting enzyme 2 (ACE2) as its primary receptor. The virus's spike (S) protein binds to ACE2 and undergoes conformational changes to facilitate membrane fusion. The S protein is cleaved by proteases such as furin and TMPRSS2, which are essential for the entry process. The cleavage of the S1–S2 boundary and the S2' site within the S2 subunit is critical for the virus to engage with the host cell and initiate fusion. The S protein is composed of two subunits, S1 and S2. S1 binds to ACE2, while S2 mediates membrane fusion. The S2 subunit contains a fusion peptide that is exposed after cleavage, allowing the virus to merge with the host cell membrane. The entry process involves two proteolytic cleavage steps: one at the S1–S2 boundary and another at the S2' site. The first cleavage occurs in the virus-producing cell, while the second occurs in the target cell. TMPRSS2, a transmembrane serine protease, is present at the cell surface and facilitates S protein activation at the plasma membrane. In contrast, cathepsin L, a lysosomal protease, mediates S2' cleavage in endosomes. The entry of SARS-CoV-2 can occur through two distinct pathways: one involving TMPRSS2 at the cell surface and another involving cathepsin L in endosomes. The S protein's structure and conformational changes are crucial for the entry process. The receptor-binding domain (RBD) of the S protein interacts with ACE2, and mutations in the RBD can affect binding affinity and viral entry. Neutralizing antibodies target the RBD and other regions of the S protein, highlighting the importance of these regions in viral entry. The review also discusses the role of ACE2 orthologues in reservoir species and the adaptations that facilitate human transmission. Additionally, it examines the potential of vaccines, antibodies, and other therapeutics targeting SARS-CoV-2 entry mechanisms. The study highlights the complex interplay between viral proteins, host receptors, and cellular processes that enable SARS-CoV-2 to infect and replicate in human cells.