Men who have sex with men (MSM) have increased rates of human immunodeficiency virus (HIV) infection and sexually transmitted diseases (STDs) compared with demographically matched controls. The reasons for the disproportionate infection burden are complex, including biological, behavioral, and sociocultural factors. HIV and syphilis may often be coprevalent among MSM. The use of nucleic acid amplification testing has enhanced the ability to detect frequently asymptomatic gonococcal and chlamydial infections of the rectum and other sites. Lymphogranuloma proctitis outbreaks among MSM were noted in the developed world several years ago but have not been common recently. MSM are at increased risk for viral hepatitis and anal human papillomavirus disease. Preventive interventions include vaccination for the former and anal cytologic screening for the latter. Because of the diverse ways in which MSM may be exposed to STDs, it is essential for clinicians to obtain a thorough sexual history in a culturally competent manner.