Abstract Epstein-Barr virus is a human herpesvirus that is a paradigm for understanding persistent infection. It infects >90% of the human population usually early in life and then remains for the life of the human host. This persistent infection is almost always benign but occasionally is associated with the development of cancers several of which constitute significant health problems. These include immunoblastic, Hodgkin's and Burkitt's lymphomas. We have presented a large body of evidence in support of a model, which is now generally accepted, of how EBV establishes and maintains this infection. The essence of this model is that EBV usurps the normal biology of the B lymphocyte. Specifically EBV uses a series of B cell stage specific transcription programs to first activate the newly infected B cell then drive it through a germinal center reaction (the site where B cells usually undergo affinity maturation of their immunoglobulin genes) to emerge as a latently infected resting memory B cell – the site of long term persistence. Ultimately reactivation of the virus from these cells occurs when they are triggered into terminal differentiation to become plasma cells. This infectious virus then becomes amplified through lytic infection of the epithelium at the mucosal surface prior to release into saliva – the vehicle via which the infection is spread. When the progression of newly infected cells into the memory compartment is compromised at any given stage this can give rise to EBV associated lymphoma. In this presentation I will review the model of EBV persistence, where and how it becomes dysregulated leading to lymphoma with especial focus on Burkitt's lymphoma This will include new evidence implicating viral miRNAs in the development of these tumors. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL01-02.