Several nucleoside and nucleotide analogues have been identified as potent antiviral agents with convincing activity against poxviruses (including variola, vaccinia, monkeypox, cowpox, molluscum contagiosum, orf). Among the nucleoside analogues, 8-methyladenosine and 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242), have been identified as promising anti-poxvirus agents. Among the nucleotide analogues, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC, cidofovir], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP] and (S)-6-(3-hydroxy-2-phosphonylmethoxypropyl)oxy-2,4-diaminopyrimidine [(S)-HPMPO-DAPy] have been identified as promising anti-poxvirus agents. These nucleoside and nucleotide analogues have proved to be efficacious in various animal models for poxvirus infections. Only one compound, cidofovir, has also proved efficacious against poxvirus infections in humans, i.e. molluscum contagiosum and orf (sheep pox). Cidofovir is formally licensed for clinical use (intravenous administration for the treatment of cytomegalovirus retinitis in AIDS patients); however, it could also be formulated for topical administration, or for oral administration in prodrug form, i.e. as 1-O-hexadecyloxypropyl-cidofovir.