Nm23-H1 was discovered as the first metastasis suppressor gene about 20 years ago. Since then, extensive work has contributed to understanding its role in various cellular signaling pathways. Its association with a range of human cancers as well as its ability to regulate cell cycle and suppress metastasis has been explored. We have determined that the EBV-encoded nuclear antigens, EBNA3C and EBNA1, required for EBV-mediated lymphoproliferation and for maintenance EBV genome extrachromosomally in dividing mammalian cells, respectively, target and disrupt the physiological role of Nm23-H1 in the context of cell proliferation and cell migration. This review will focus on the interaction of Nm23-H1 with the Epstein-Barr virus nuclear antigens, EBNA3C and EBNA1 and the functional significance of this interaction as it relates to EBV pathogenesis.