The recognition that smallpox is a potential threat agent of bioterrorism has engendered renewed interest in the development of improved vaccines against this pathogen. The purpose of this paper is to review current data regarding novel approaches to smallpox vaccines in comparison with traditional vaccine strategies. The method used is a literature search using overlapping search terms and citations from the relevant, published literature. Substantial animal and limited human data suggest that selected second and third generation smallpox vaccines, specifically tissue‐cultured vaccinia virus and replication‐competent, highly attenuated vaccinia virus possess immunogenicity and surrogate efficacy profiles similar to those of first generation New York City Board of Health and Lister vaccines. Replication‐defective, attenuated vaccinia appears to be less immunogenic in both animals and humans but may have utility as a priming agent in those with contraindications to live vaccinia. There is a clear risk of myopericarditis with first and second generation products, but the relative risk of this complication among various vaccine approaches cannot as yet be determined. The incidence of other serious, albeit uncommon, adverse events of smallpox vaccines cannot be determined for newer vaccine approaches because these agents have not yet been deployed on a scale large enough to discern rare events. Since 2001, progress towards improved smallpox vaccines has been accelerated, spurred on by the threat of bioterrorism. Among newer vaccine candidates, replication‐competent, highly attenuated vaccinia and tissue culture‐derived live vaccinia appear to offer the greatest potential for efficacy, although it is unclear whether these products offer a safer alternative to existing first generation vaccines. Copyright © 2008 John Wiley & Sons, Ltd.