The mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tract are entry points for a variety of pathogens and they serve as the first line of defense against infection. To prevent transmission of mucosal pathogens, it is often necessary to target the vaccine to the mucosal surface. Viral vectors, such as poxviruses expressing gene inserts, capable of overcoming the formidable array of host defenses at the mucosal surfaces, are an attractive vaccination strategy for mucosal immunization against infectious diseases. Replication-competent vectors, such as vaccinia, are highly effective, but have a number of safety concerns that may limit their widespread use in humans. In contrast, replication-deficient vectors, such as modified vaccinia ankara (MVA), ALVAC, and NYVAC, may be safer vectors than live vectors, but these vectors may not be as effective at inducing immune responses. Co-delivery of viral vectors with genetic adjuvants (cytokines) or deletion of certain immunomodulatory genomic sequences from these viral vectors may increase vaccine efficiency and are promising strategies for a new generation of mucosal vaccines.