Chlamydia trachomatis sexually transmitted infections cause considerable morbidity and socioeconomic burden worldwide, despite significant advances in our understanding of the biology (29, 31, 57), pathogenesis (11, 83, 117), genomics (94), and epidemiology (91) of this parasite. Chlamydial urogenital tract infections are readily cured with antibiotics, but control measures based on antimicrobial chemotherapy alone are hampered by the frequency of asymptomatic infections and delayed diagnosis (9). Definitive control of C. trachomatis sexually transmitted diseases (STDs) is possible through the development of a safe and efficacious vaccine (24). Progress toward the development of an effective vaccine has been disappointingly modest, as it has been for vaccines to other sexually transmitted pathogens that infect the genital tract mucosae. The strict tropism for mucosal epithelial cells, the complex biology and antigenic structure, and the predilection to cause persistent infection have presented formidable challenges to chlamydial vaccine development. A heightened understanding of protective immunity to C. trachomatis urogenital infection has emerged in the past decade from studies using a mouse model of chlamydial genital tract infection. The insights are of considerable interest because they offer promise for the development of an efficacious chlamydial vaccine. This review focuses on that progress and summarizes the current understanding of protective immune mechanisms that function against murine chlamydial urogenital infection. We also discuss specific requirements for a vaccine to protect against chlamydial STDs and the challenges presently confronting us in achieving that goal.