Epstein-Barr virus (EBV) causes infectious mononucleosis and oral hairy leucoplakia, and is associated with a number of malignancies. There are, however, no regulatory agency-approved treatments for EBV-related diseases. Several antiviral drugs inhibit replication of EBV in cell culture including acyclic nucleoside and nucleotide analogues and pyrophosphate analogues, all of which inhibit the EBV DNA polymerase. Despite their potency in vitro, these drugs have limited use in vivo for treatment of acute primary EBV infection as well as EBV-associated malignancies for several reasons. Here we discuss novel anti-EBV compounds, including maribavir, potentially useful for the treatment of acute EBV infections. A number of experimental approaches for treatment of EBV-related malignancies that are not susceptible to conventional antiviral drug treatment are also discussed.