Recent advances reveal that mitochondria are not limited to functioning only as the cellular powerhouse and in apoptosis, but that they act as central hubs for multiple signal transductions. Studies over the last decade indicate that mitochondria in vertebrates are involved in the front line of host defense, especially against RNA viruses. Mitochondrial-mediated antiviral innate immunity depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway, and the mitochondrial surface acts as a platform for the assembly of signaling molecules, including mitochondrial antiviral signaling (MAVS) during the process. Some viral encoded proteins target to the mitochondria post-infection, however, thereby evading the cellular immune response. Here we review specific interactions between mitochondria and viral proteins and discuss their physiologic effects on the host cells.