This review provides a comprehensive overview of the mechanisms by which SARS-CoV-2 enters host cells, focusing on the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. The S protein, which is cleaved into two subunits (S1 and S2) during viral maturation, plays a crucial role in this process. The S1 subunit binds to ACE2, while the S2 subunit anchors the S protein to the viral membrane and facilitates membrane fusion. The review discusses the structural and cellular foundations of this multistep process, including the conformational transitions of the S protein, the role of proteases such as furin-like proteases, TMPRSS2, and cathepsin L, and the features of ACE2 orthologues in reservoir animal species. It also examines the potential of vaccines, antibodies, and other therapeutics targeting these entry mechanisms. Finally, the review highlights key outstanding questions in this critical area of research.This review provides a comprehensive overview of the mechanisms by which SARS-CoV-2 enters host cells, focusing on the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. The S protein, which is cleaved into two subunits (S1 and S2) during viral maturation, plays a crucial role in this process. The S1 subunit binds to ACE2, while the S2 subunit anchors the S protein to the viral membrane and facilitates membrane fusion. The review discusses the structural and cellular foundations of this multistep process, including the conformational transitions of the S protein, the role of proteases such as furin-like proteases, TMPRSS2, and cathepsin L, and the features of ACE2 orthologues in reservoir animal species. It also examines the potential of vaccines, antibodies, and other therapeutics targeting these entry mechanisms. Finally, the review highlights key outstanding questions in this critical area of research.