Viral genome replication in Flaviviridae is carried out by a virally encoded RNA-dependent RNA polymerase (RdRp). These viruses initiate the RNA synthesis via a de novo mechanism that differs from the primer-dependent mechanism used by Picornaviridae. Like all polymerases, the structure of Flaviviridae RdRps resembles a right hand with characteristic fingers, palm, and thumb domains. Structural features that distinguish Flaviviridae RdRps from other polymerases are a large thumb domain and a C-terminal motif that encircles the active site. This domain arrangement restricts the volume of the template-binding channel, allowing only single-stranded RNA to enter the active site. While this closed form of the polymerase is ideal to stabilize a de novo initiation complex, significant conformational changes are expected to accommodate the elongation complex containing the RNA duplex product.