Sexually transmitted infections (STIs) comprise more than 30 different bacterial, viral, protozoal, and yeast infections acquired during sexual intercourse and therefore directly afflicting the genital tracts or gaining systemic access across the genital mucosae. Effective vaccines have been developed against only two viral STIs (hepatitis B and human papillomavirus). For most STIs, the nature of the immune responses induced and the parameters of immunity against them are poorly understood. However, progress has been made in comprehending responses especially against Neisseria gonorrhoeae, Chlamydia trachomatis, Haemophilus ducreyi, and Candida albicans. An emerging aspect is that these well-adapted human pathogens exploit the unique characteristics of immunity in the reproductive tracts, eliciting responses favorable to their own survival and suppressing those that would be detrimental to them. Elucidation of the mechanisms whereby STI pathogens manipulate the host's immune responses will lead to novel approaches for therapy and vaccine development.