The Centers for Disease Control and Prevention (CDC) Sexually Transmitted Disease (STD) Treatment Guidelines were last updated in 2006. To update the "Clinical Guide to Prevention Services" section of the 2010 CDC STD Treatment Guidelines, we reviewed the recent science with reference to interventions designed to prevent acquisition of STDs, including human immunodeficiency virus (HIV) infection. Major interval developments include (1) licensure and uptake of immunization against genital human papillomavirus, (2) validation of male circumcision as a potent prevention tool against acquisition of HIV and some other sexually transmitted infections (STIs), (3) failure of a promising HIV vaccine candidate to afford protection against HIV acquisition, (4) encouragement about the use of antiretroviral agents as preexposure prophylaxis to reduce risk of HIV and herpes simplex virus acquisition, (5) enhanced emphasis on expedited partner management and rescreening for persons infected with Chlamydia trachomatis and Neisseria gonorrhoeae, (6) recognition that behavioral interventions will be needed to address a new trend of sexually transmitted hepatitis C among men who have sex with men, and (7) the availability of a modified female condom. A range of preventive interventions is needed to reduce the risks of acquiring STI, including HIV infection, among sexually active people, and a flexible approach targeted to specific populations should integrate combinations of biomedical, behavioral, and structural interventions. These would ideally involve an array of prevention contexts, including (1) communications and practices among sexual partners, (2) transactions between individual clients and their healthcare providers, and (3) comprehensive population-level strategies for prioritizing prevention research, ensuring accurate outcome assessment, and formulating health policy.