The use of Salmonella spp. as a delivery system for foreign antigens represents a unique opportunity for the development of ideal vaccines with unparalleled merits. Increased understanding of the mechanisms underlying Salmonella virulence and host immune response will continuously create novel strategies for more effective Salmonella-based vaccines. However, limitations in our capability to manipulate the genome of a vector strain efficiently have delayed the realization of vaccination ideas. Owing to the development of new technologies in recent years, it has now become feasible to rapidly construct Salmonella vaccine strains that carry precise modifications on the chromosomal DNA. This technical advancement will open a new avenue for the effective development of Salmonella-based vaccines for infectious diseases of both human and animal health importance.