One class of compounds that has shown promise as antiviral agents are the (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides, members of the broader class of acyclic nucleoside phosphonates. These HPMP nucleosides are nucleotide analogs and have been shown to be effective inhibitors of a wide range of DNA viruses. Prodrugs of these compounds, which achieve higher levels of the active metabolites within the cell, have an expanded activity spectrum that also includes RNA viruses and retroviruses. Because they are analogs of natural nucleotide substrates, HPMP nucleosides are predicted to target polymerases (DNA polymerases, RNA polymerases and reverse transcriptases), resulting in the inhibition of viral genome replication. Previous work using the replicative enzymes of different viruses including human cytomegalovirus (HCMV) and vaccinia virus DNA polymerases and human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has shown that the activated forms of these compounds are substrates for viral polymerases and that incorporation of these compounds into either the primer strand or the template strand inhibits, but does not necessarily terminate, further nucleic acid synthesis. The activity of these compounds against other viruses that do not encode their own polymerases, like polyoma viruses and papilloma viruses, suggests that host cell DNA polymerases are also targeted. This complex mechanism of action and broad activity spectrum has implications for the development of resistance and host cell genome replication, and suggests these compounds may be effective against other viruses such as influenza virus, respiratory syncytial virus and Dengue virus. This class of nucleotide analogs also points to a potential avenue for the development of newer antivirals.