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Halting transmission The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein binds to host cells and initiates membrane fusion and cell infection. This stage in the virus life history is currently a target for drug inhibition. De Vries et al. designed highly stable lipoprotein fusion inhibitors complementary to a conserved repeat in the C terminus of S that integrate into host cell membranes and inhibit conformational changes in S necessary for membrane fusion. The authors tested the performance of the lipoproteins as a preexposure prophylactic in a ferret-to-ferret transmission study. Intranasal administration of the peptide 2 days before cohousing with an infected ferret for 24 hours completely protected animals in contact from infection and showed efficacy against mutant viruses. Because ferrets do not get sick from SARS-CoV-2, disease prevention could not be tested in this model. Science, this issue p. 1379, A dimeric form of a SARS-CoV-2–derived lipopeptide is a potent inhibitor of fusion and infection in vitro and transmission in vivo., Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.