Introduction Direct-acting SARS-CoV-2 antiviral monoclonal antibodies have been an integral part of therapeutic strategies implemented to combat the COVID-19 pandemic. However, the monoclonal strategy was jeopardized by the frequent emergence of new variants and resistant strains, caused by the massive spread of the virus. Many monoclonal antibodies have quickly become obsolete. Nevertheless, a possible strategy to improve their longevity consists of the use of antibody cocktails and the development of the cilgavimab + tixagevimab in combination is placed in this context. Areas covered In this review, the authors describe the pre-clinical and clinical development of the cilgavimab + tixagevimab cocktail, and its approval in the prophylaxis and, more recently, in the treatment of COVID-19. They furthermore discuss its positioning in the therapeutic armamentarium. Expert opinion The pre-clinical and clinical development of cilgavimab + tixagevimab followed a similar path to that of the antibodies developed in the earlier stages of the pandemic. Both antibodies have been developed from convalescent plasma and have been shown to be effective in clinical trials in prophylaxis and in early therapy. This cocktail has found its position in therapy especially in immunocompromised subjects for whom vaccine prevention is not feasible. The cocktail strategy, together with a more stable pandemic situation, could ensure a certain longevity to the drug against resistance, especially when compared with that of other antibodies. However, recently emerged Omicron sub-lineages have demonstrated the ability to escape this cocktail’s activity and so the future of this treatment could be compromised.