Epstein-Barr virus is a ubiquitous gammaherpesvirus that usually causes an asymptomatic infection followed by lifelong persistence in memory B cells. Virus replication is controlled by a robust antiviral immune response, and EBV-associated lymphoproliferative diseases only develop in immunocompromised individuals. However, systemic chronic active Epstein-Barr virus (CAEBV) disease occurs in individuals without an apparent immunodeficiency or an underlying genetic immune defect. These individuals cannot control EBV infection, leading to life-threatening conditions including haemophagocytic lymphohistiocytosis, organ failure and malignant lymphomas. CAEBV disease is characterized by systemic inflammation, markedly elevated EBV DNA load in the blood, clonal expansion of EBV-infected T cells and/or NK cells, and multi-organ infiltration by the infected cells. Here we summarize the current understanding of the pathogenesis of systemic CAEBV disease, identifying viral, genetic and immunologic changes that could be integral to disease development and progression, as well as targeted by future precision medicine.