Chlamydia is the most common sexually transmitted bacterial infection in humans but is often asymptomatic. Left untreated, chlamydia infection can lead to serious complications, such as infertility, and thus vaccine development is a priority. Morrison et al. studied Chlamydia muridarum infection in mice, isolating a mutant C. muridarum strain (termed GIAM-1) that shows substantially reduced infection of the genital tract compared with that of the wild type. However, GIAM-1 efficiently infected the gastrointestinal tract, which induced robust humoral immunity against C. muridarum. Importantly, gastrointestinal tract infection with GIAM-1 protected mice against subsequent genital tract infection with wild-type C. muridarum. These results suggest that by manipulating tissue-tropism to obtain immunogenic bacterial strains that do not infect the genital tract, a live-attenuated vaccine for the human pathogen Chlamydia trachomatis might be obtainable.