Due to the oncogenic potential associated with persistent infection of human gamma-herpesviruses, including Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), vaccine development has focused on subunit vaccines. However, the results using an animal model of mouse infection with a related rodent virus, murine gamma-herpesvirus 68 (MHV-68, γHV-68, or MuHV-4), have shown that the only effective vaccination strategy is based on live attenuated viruses, including viruses engineered to be incapable of establishing persistence. Vaccination with a virus lacking persistence would eliminate many potential complications. Progress in understanding persistent infections of EBV and KSHV raises the possibility of engineering a live attenuated virus without persistence. Therefore, we should keep the option open for developing a live EBV or KSHV vaccine.