Hepatitis delta virus (HDV) is an infectious, subviral, pathogen that is associated with a high incidence of fulminant hepatitis in humans. It consists of a closed-circular, single-stranded, RNA genome of about 1700 nucleotides in length that is replicated by a rolling-circle mechanism (reviewed by refs. 1 and 2 ). There is no DNA intermediate. The infectious genomic strand is a template for an RNA-dependent RNA polymerase (most likely a modified activity of the host’s RNA polymerase II) that generates linear single-stranded multimers of the antigenomic sense. These linear multimers are site-specifically cleaved and ligated to form the closed-circular antigenomic RNAs, which are likewise templates for rolling-circle replication. The linear genomic multimers are also site-specifically cleaved and ligated, and the resulting circular RNAs are subsequently encapsulated to form new infectious particles.