The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, and escape mechanisms. Antibodies targeting the receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in SARS-CoV-2 variants. In contrast, antibodies targeting conserved regions, such as the S2 stem helix and fusion peptide, exhibit broader reactivity but generally lower neutralization potency. However, several broadly neutralizing antibodies have demonstrated exceptional efficacy against emerging variants, including the latest omicron subvariants, underscoring the potential of targeting vulnerable sites such as RBS-A and RBS-D/CR3022. We also highlight public classes of antibodies targeting different sites on the S protein. The vulnerable sites targeted by public antibodies present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent antibodies and broadly effective vaccines remains crucial for combating future variants. This review emphasizes the importance of identifying key epitopes and utilizing antibody affinity maturation to inform future therapeutic and vaccine design.