Endemic Burkitt's lymphoma (BL) remains the most prevalent pediatric cancer in sub-Saharan Africa even though it was the first human cancer with a viral etiology described over 50 years ago. Epstein-Barr virus (EBV) was discovered in a BL tumor in 1964 and has since been implicated in other malignancies. The etiology of endemic BL has been linked to EBV and Plasmodium falciparum malaria co-infection. While epidemiologic studies have yielded insight into EBV infection and the etiology of endemic BL, the modulation of viral persistence in children by malaria and deficits in EBV immunosurveillance has more recently been reified. Renewed efforts to design prophylactic and therapeutic EBV vaccines provide hope of preventing EBV-associated BL as well as increasing the ability to cure this cancer.