Antiviral agents are being sought as countermeasures for the potential deliberate release of smallpox (variola) and monkeypox viruses, for the treatment of naturally acquired monkeypox virus infections, and as therapy for complications due to smallpox (live-attenuated vaccinia virus) vaccination or accidental infection after exposure to vaccinated persons. Reviews of the scientific literature spanning 1950–2008 have documented the progress made in developing small-animal models of poxvirus infection and identifying novel antiviral agents. Compounds of considerable interest include cidofovir, CMX001 and ST-246® (tecovirimat; SIGA Technologies, NY, USA). New inhibitors have been identified since 2008, most of which do not exhibit the kind of potency and selectivity required for drug development. Two promising agents include 4´-thio-idoxuridine (a nucleoside analog) and mDEF201 (an adenovirus-vectored interferon). Compounds that have been effectively used in combination studies include vaccinia immune globulin, cidofovir, ST-246 and CMX001. In the future there may be an increase in experimental work using active compounds in combination.