Early research on Epstein-Barr virus (EBV) developed from serological observations that were made soon after the discovery of the virus. Indeed, the definition of the humoral response to a variety of EBV proteins dominated the early literature and was instrumental in providing the key evidence for the association of the virus with infectious mononucleosis (IM), Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC). Each of these disease associations involved a distinct pattern of serological reactivity to the EBV membrane antigens (MA), early antigens (EA), and the EBV nuclear antigen (EBNA). When it became generally accepted that the marked lymphocytosis , which is a hallmark of acute IM, was dominated by T cells, considerable effort was directed toward untangling the specificities that might be associated with restricting the proliferation of newly infected B cells. Early evidence was divided between support for both EBV non-specific and/or HLA non-restricted components. However, all results needed to be reassessed in light of the observation that T cells died by apoptosis within hours of separation from fresh blood from acute IM patients. The observation that EBV-infected cultures from immune (but not non-immune) individuals began to die (termed regression) about 10 days post-seeding, provided the first evidence of a specific memory response which was apparently capable of controlling the small pool of latently infected B cells which all immune individuals possess. In this early era, CD8(+) T cells were thought to be the effector population responsible for this phenomenon, but later studies suggested a role for CD4(+) cells. This historical review includes reference to key early observations in regard to both the specific humoral and cellular responses to EBV infection from the time of the discovery of the virus until 1990. As well, we have included personal recollections in regard to the events surrounding the discovery of the memory T cell response since we believe they add a human dimension to a chapter focussed on early history.