The recent 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 interaction of viruses with the RNAi machinery in mammalian cells. We have shown that members of two different DNA tumor virus families encode microRNAs; likely to aid in their own replication and to promote infectivity. SV40 induces tumors in model organisms and Kaposi's Sarcoma Associated Herpes Virus (KSHV) promotes highly vascularized skin tumors and rare B cell lymphomas, predominantly in immunosuppresed AIDs patients. Our goals are twofold: (1) to understand the functions of viral and host encoded microRNAs and how they contribute to viral lifecycle, pathogenesis and tumorigenesis, and (2) to identify novel interactions of mammalian viruses with the host RNAi machinery.