Declaration of smallpox eradication by the WHO on 1980 led to discontinuation of the world-wide vaccination campaign. The increasing percentage of unvaccinated individuals, the existence of its causative infectious agent variola virus (VARV) and the recent synthetic achievements, increases the threat of intentional or accidental release and reemergence of smallpox. Control of smallpox would require an emergency vaccination campaign as no other protective measure has been approved to achieve eradication and ensure world-wide protection. Experimental data in surrogate animal models support the assumption, based on anecdotal, uncontrolled historical data, that vaccination up to 4 days postexposure, confers effective protection. The long incubation period and the uncertainty of the exposure status in the surrounding population calls for the development and evaluation of safe and effective methods that would allow to extend the therapeutic window and to reduce the disease manifestations and vaccine adverse reactions. To achieve these goals, we need to evaluate the efficacy of novel and already licensed vaccines as a sole treatment or in conjunction with immune modulators and antiviral drugs. In this review, we address the available data, recent achievements and open questions.