Current vaccines for COVID-19 induce immune responses to immunodominant but highly variable SARS-CoV-2 epitopes. Given the continuing emergence of variants of concern and threat of zoonotic spillovers, pan-protective monoclonal antibodies (mAbs) are highly desirable. A report in Nature by Tortorici et al. now describes a human mAb (S2X259) that binds a highly conserved cryptic receptor-binding domain epitope of SARS-CoV-2. S2X259 cross-reacts with spike proteins from all four sarbecovirus clades and protected Syrian hamsters from challenge with prototypic SARS-CoV-2 and with the SARS-CoV-2 beta variant. Apart from identifying S2X259 as a promising candidate for clinical development, the discovery of a target site for broadly neutralizing antibodies may also guide efforts to develop pan-sarbecovirus vaccines that protect against SARS-CoV-2 variants and future cross-species transmission.