With spillover of several coronaviruses to humans in the past few decades and continued evolution of variants, developing ‘pan-coronavirus’ antibodies and vaccines remains a high priority. To find such a broadly neutralizing antibody, Sun et al. screened the plasma from previously infected individuals for binding to the S2 region of spike from SARS-CoV, SARS-CoV-2 and MERS-CoV, which is more conserved than the receptor-binding domain-containing S1. One sample showed cross-reactivity, also against spike proteins of seasonal CoVs. The authors then isolated a monoclonal antibody, 76E1, from this individual and showed that it neutralizes all variants of concern up to Omicron BA.1 in vitro. Furthermore, 76E1 showed therapeutic activity against SARS-CoV-2 and a phylogenetically removed seasonal coronavirus. Structural work showed that 76E1 targets a highly conserved epitope in the prefusion spike complex that is exposed during receptor binding.