The presence of endogenous oncornavirus and herpesvirus in guinea pigs has been established. The oncornavirus apparently is present in all guinea pigs but is expressed only under certain conditions. Expression of the latent herpesvirus is generally age and strain dependent as is the development of spontaneous guinea pig leukemia. Following special laboratory manipulation, expression of both virus types was accomplished in vitro. Studies of the role played by these two virus types in the development of neoplastic disease in guinea pigs revealed that, in the presence of the endogenous oncornavirus, a superinfection with herpesvirus led to the development of self-limited lymphoproliferative changes. Together with the studies reported by other investigators, it appears that interaction between the DNA and RNA viruses may play an important role in the natural occurrence of viral oncogenesis. Guinea pigs provide an intriguing animal model for the study of herpesvirus and oncornavirus interaction both in vivo and in vitro.