RNA interference or RNA silencing is a dsRNA guided mechanism that mediates sequence specific degradation of RNA. The recent demonstration that RNA interference can be used to inhibit virus replication has initiated an exciting field of research: first, as a potential novel antiviral therapeutic approach and, second, as a tool for dissecting virus-host interactions. Here we review and discuss the current data and perspectives on the use of RNA interference in the study of poliovirus as a model for positive strand RNA viruses.