Many RNA viruses cause both acute and persistent infections, but little is known of the mechanisms that underlie persistence. Using the parainfluenza virus type 5 (PIV5) as a model for paramyxoviruses, Young et al. found that the phosphorylation status of the P protein of the viral RNA polymerase complex determines whether viral transcription and replication become repressed at late times during infection. If repression occurs, a persistent infection is established, which fluxes between active and repressed states, and if not, the infected cell dies. The switch from acute to persistent infection was affected by single amino acid substitutions that prevent phosphorylation of the P protein. Viruses with a mutation at a specific phosphorylation site replicated to higher titres in mice, caused greater immune responses, but were cleared more quickly. The authors propose that during acute infection, lytic variants are selected, but later, the immune response selects for variants that promote persistence.