Three studies published in this issue of Cell reveal that multiple MERS-related coronaviruses (MERSr-CoVs) utilize ACE2, rather than the canonical Merbecovirus receptor DPP4, for cell entry. These ACE2-dependent MERSr-CoVs pose a risk of zoonotic transmission to humans with high transmissibility potential like SARS-CoV-2, thus calling for global surveillance and countermeasures.