The Epstein-Barr virus (EBV) has been implicated in the aetiology of many human lymphoid and epithelial malignancies. Although EBV is B lymphotropic in vitro, it has been hypothesised that oropharyngeal epithelium is important in primary EBV infection, replication, and persistence in vivo, and that infection of B lymphocytes is secondary. This hypothesis has been challenged by several recent studies. On the basis of current evidence, we propose that primary EBV infection and virus persistence are mediated through B lymphocytes, and that latent infection of epithelial cells is accidental and irrelevant to virus persistence, although important in the development of certain carcinomas. To what extent T cells are involved in EBV persistence remains uncertain. Clarification of the possible part played by EBV in the development of virus-associated tumours requires a better understanding of the mode of EBV persistence and the identification of the stage in the carcinogenic process at which EBV infection occurs.