This chapter discusses how bacterial genetics and recombinant DNA techniques are being combined to develop new attenuated bacterial vaccine strains and in turn, how these vaccine strains are being used to construct multivalent vaccines that express genes for protective antigens. Formal and colleagues were the first to use Salmonella as a multivalent vaccine by introducing Shigella sonnei antigens into Ty21a. Vaccination with Shigella–Salmonella hybrids demonstrated that a Salmonella derivative that expresses Shigella group-specific antigen could result in antibody response against the group-specific antigen. Expression of E. coli β-galactosidase in Salmonella, a cytoplasmic protein, results in a cellular response against β-galactosidase as well as a humoral response. This result shows that a cellular response can be induced against heterologous antigens and also shows that an antigen need not be expressed on the bacterial cell surface to generate a strong response. In this regard, the immune response to bacteria may be similar to the immune response to influenze virus. The chapter focuses on attenuated vaccines for the facultative intracellular pathogens, Salmonella typhimurium, S. typhi, and Mycobacterium tuberculosis, because they show particular promise for the construction of multivalent vaccines. It also includes the current status of live vaccines for pathogenic Brucella, Shigella, and Vibrio cholerae.