Epstein-Barr virus (EBV) is a large lymphotrophic DNA virus that establishes life-long residency in the infected host and is associated with a number of human tumors. The EBV genome encodes proteins essential for persistence, an oncoprotein, and proteins that render it vulnerable to the host's immune system; therefore, EBV gene transcription is tightly regulated. One critically important regulatory mechanism utilized by EBV is DNA methylation. Methylation of cytosines within CpG dinucleotides at promoter regions is important for gene silencing and genome integrity. Although most parasitic elements are methylated in mammalian cells never to be reactivated again, EBV has evolved to utilize DNA methylation to maximize persistence and cloak itself from immune detection. EBV's reliance on DNA methylation also provides a unique therapeutic strategy for the treatment of EBV-associated tumors. DNA demethylating agents are capable of reactivating transcription of highly immunogenic viral proteins, rendering tumor cells susceptible to killing by the host immune system, and inducing the viral lytic cycle which culminates in cell lysis. (C) 2003 Elsevier Inc. All rights reserved.