Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer prevalent in Southeast Asia and Southern China, where it constitutes a significant health burden. Although the close association of NPC with Epstein-Barr virus (EBV) infection has been known for more than four decades, the exact role that EBV plays in the pathogenesis of this malignancy is still unclear. While NPC tumors are known to express a number of EBV-encoded proteins, they also express a large number of virus-encoded microRNAs (miRNAs), the most abundant of which are those encoded from the BamHI-A region of the viral genome: the so-called BART miRNAs. miRNAs are small non-coding mRNAs that negatively regulate the expression of various genes at the post-transcriptional level. Accumulating evidence suggests that miRNAs play important roles in tumorigenesis. Here, we review the role of EBV-encoded BART miRNAs in modulating apoptosis and host innate defense mechanisms and their contribution to NPC pathogenesis. The rationale and the strategies for therapeutic targeting of BART miRNAs in EBV infected NPC are also discussed. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.