Typhoid fever remains an important public health problem in many parts of the world. Despite the availability of oral Ty21a (Vivotif; Berna Biotech) and parenteral Vi polysaccharide vaccine (Typhim Vi; Aventis Pasteur), improved typhoid fever vaccines have been sought. These include a series of vaccine candidates developed at the Center for Vaccine Development, University of Maryland, based on attenuation of Salmonella enterica serovar Typhi by deletions in the aroC, aroD, and htrA genes. These vaccine candidates, designated "CVD 908," "CVD 908-htrA," and "CVD 909," have been developed and tested in volunteers with variable success. This review summarizes the clinical data that directed the logical progression of this vaccine development strategy.