Epstein Barr virus (EBV) is a human γ-herpesvirus that was discovered in Burkitt's lymphoma more than 50 years ago. Since then it has been proposed as the causative agent of up to 2% of all tumors worldwide, mainly lymphomas and epithelial cell carcinomas. Surprisingly, persistent EBV infection is at the same time found in more than 90% of healthy human adults. Even the very same programs of EBV infection that are found in the associated malignancies are continuously present in healthy EBV carriers. We will discuss primary immunodeficiencies and immune compartment changes during the first decade of human life that give us insights into how tumorigenesis by persistent EBV infection and Hodgkin's lymphoma predisposing infectious mononucleosis is prevented during primary infection. These insights should allow identifying individuals at risk to develop EBV associated malignancies, who would benefit from EBV specific vaccination.