The discovery of RNA interference (RNAi) and small regulatory RNAs such as siRNAs and miRNAs, has dramatically changed our understanding of the regulation of gene expression. Consequently, RNAi has generated much excitement due to its regulatory and therapeutic potential. Our research focuses on understanding the role of non-coding RNA in virus infection including interaction of viruses with the RNAi machinery in mammalian cells. We have shown that members of different tumor virus families (including Polyomaviridae, Herpesviridae, and Retroviridae) encode microRNAs; likely to aid in their own replication and to promote infectivity. Members of the Polyoma virus family induce tumors in model organisms and at least one member (MCV) is associated with human tumors. Kaposi's Sarcoma associated Herpes Virus (KSHV) promotes highly vascularized skin lesions and rare B cell lymphomas, predominantly in immunosuppresed AIDS patients. Our goals are several-fold: (1) to understand the functions of viral and host encoded non-coding RNAs and how they contribute to viral lifecycle, pathogenesis and tumorigenesis, (2) to identify novel interactions of mammalian viruses with the host RNAi machinery, (3) to uncover new mechanisms of gene regulation utilized by tumor viruses and the host in response to infection, and (4) to use viruses as "molecular divining rods" to probe for new classes of host defense pathways.