It is estimated that approximately 20 million new sexually transmitted infections (STIs) occur each year in the United States. The federally funded sexually transmitted disease prevention program implemented by Centers for Disease Control and Prevention is primarily focused on the prevention and control of the three most common bacterial STIs: syphilis, gonorrhea, and chlamydia. A range of factors facilitate the transmission and acquisition of STIs, including syphilis. In 1999, Centers for Disease Control and Prevention launched the National Campaign to Eliminate Syphilis from the United States. The strategies were familiar to public health in general and to sexually transmitted disease control in particular: (1) enhanced surveillance, (2) expanded clinical and laboratory services, ((3) enhanced health promotion, (4) strengthened community involvement and partnerships, and (5) rapid outbreak response. This national commitment to syphilis elimination was not the first effort, and like others before it too did not succeed. However, the lessons learned from this most recent campaign can inform the way forward to a more comprehensive approach to the prevention and control of STIs and improvement in the nation's health.