It has been nearly 20 years since the first Phase I clinical trial of a live-attenuated bacterial vaccine was created by recombinant DNA methods, opening the door to the use of these organisms as mucosal delivery vehicles for passenger antigens. Over this time, a number of animal studies have indicated the feasibility of this approach. These include studies showing that bacteria can deliver antigens expressed by the bacterium itself and that bacteria can deliver DNA vaccines to be expressed in target eukaryotic cells. Concomitant studies have identified a number of attenuating mutations that render the bacterial vectors both safe and immunogenic in humans. Both avenues of research indicate the significant promise of this approach to mucosal vaccine development; however, this promise remains largely unrealized at the level of human clinical trials. This review sketches the history of this problem and points toward possible solutions using Salmonella vaccine vectors as the prototypes.