Classic viral pathogenesis models postulate that tissues supporting efficient virus replication promote virus dissemination, which culminates in clinical illness. In this issue of Cell Host & Microbe, Sacher and colleagues use Cre/loxP recombination to label murine cytomegalovirus during replication in distinct cell types in vivo. Strikingly, they demonstrate that the most productive cell type in the host—the hepatocyte—contributes no progeny to dissemination to other tissues.