Sotrovimab, a monoclonal antibody (mAb) derived from S-309, has shown high efficacy against SARS-CoV-2 variants, particularly in outpatients. It targets a highly conserved epitope in the Spike protein, making it resilient to viral evolution until the emergence of the BA.2.86* variant. Clinical trials, including the COMET-ICE RCT, demonstrated significant reductions in hospitalization and mortality among unvaccinated, high-risk patients. However, sotrovimab's use in immunocompromised individuals led to the selection of variants that resisted its binding, ultimately leading to its deauthorization by the FDA in April 2022. Despite this, some authorities continue to promote its use based on real-world evidence. The story of sotrovimab highlights the potential of mAbs as therapeutics but also underscores the need for strategies to minimize resistance emergence. Future research should focus on combining mAbs with other treatments to enhance their effectiveness and longevity.Sotrovimab, a monoclonal antibody (mAb) derived from S-309, has shown high efficacy against SARS-CoV-2 variants, particularly in outpatients. It targets a highly conserved epitope in the Spike protein, making it resilient to viral evolution until the emergence of the BA.2.86* variant. Clinical trials, including the COMET-ICE RCT, demonstrated significant reductions in hospitalization and mortality among unvaccinated, high-risk patients. However, sotrovimab's use in immunocompromised individuals led to the selection of variants that resisted its binding, ultimately leading to its deauthorization by the FDA in April 2022. Despite this, some authorities continue to promote its use based on real-world evidence. The story of sotrovimab highlights the potential of mAbs as therapeutics but also underscores the need for strategies to minimize resistance emergence. Future research should focus on combining mAbs with other treatments to enhance their effectiveness and longevity.