Many acute viral infections can be controlled by vaccination; however, vaccinating against persistent infections remains problematic. Herpesviruses are a classic example. Here, we discuss their immune control, particularly that of gamma-herpesviruses, relating the animal model provided by murid herpesvirus-4 (MuHV-4) to human infections. The following points emerge: (i) CD8(+) T-cell evasion by herpesviruses confers a prominent role in host defence on CD4(+) T cells. CD4(+) T cells inhibit MuHV-4 lytic gene expression via gamma-interferon (IFN-gamma). By reducing the lytic secretion of immune evasion proteins, they may also help CD8(+) T cells to control virus-driven lymphoproliferation in mixed lytic/latent lesions. Similarly, CD4(+) T cells specific for Epstein-Barr virus lytic antigens could improve the impact of adoptively transferred, latent antigen-specific CD8(+) T cells. (ii) In general, viral immune evasion necessitates multiple host effectors for optimal control. Thus, subunit vaccines, which tend to prime single effectors, have proved less successful than attenuated virus mutants, which prime multiple effectors. Latency-deficient mutants could make safe and effective gamma-herpesvirus vaccines. (iii) The antibody response to MuHV-4 infection helps to prevent disease but is suboptimal for neutralization. Vaccinating virus carriers with virion fusion complex components improves their neutralization titres. Reducing the infectivity of herpesvirus carriers in this way could be a useful adjunct to vaccinating naive individuals with attenuated mutants.