There are many insults that result in gastrointestinal tract inflammation. Infections can be particularly challenging because (1) only a limited number of organisms provoke a specific endoscopic and/or histologic appearance; and (2) although some organisms may be present on biopsies, the findings may be so subtle or organisms so few that they are easily missed if the reviewer is not performing a specific search for the offender. Sexually transmitted infections (STI) are rarely a consideration at the time of GI biopsy examination and clinicians rarely inquire about sexual behavior at the time of initial patient interview. Although establishing a definitive STI diagnosis is not possible on histology alone, these infections are associated with inflammatory patterns that may help raise this diagnostic possibility. Becoming familiar with these patterns is necessary as worldwide outbreaks of these infections are being reported. This review aims to provide the pathologist with histologic clues associated with the most frequently encountered bacterial pathogens in the setting of STI proctitis, namely, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum.