Reconfiguring and refocusing syphilis control and prevention programs in the United States is required by the changing epidemiology and sociology of syphilis as well as by the importance and magnitude of human immunodeficiency virus (HIV) prevention efforts. An updated strategic approach to syphilis prevention might involve three categories, or tiers, of prevention activities. Tier 1 activities involve the basic elements or tools of prevention programs, such as screening, treatment, partner notification, or behavior change counseling. Tier 2, or prevention effectiveness activities, represent ways to select among the basic prevention elements and to specify how they should be applied in particular epidemiologic situations to yield the greatest impact on disease transmission and persistence from available resources. Tier 3 involves strategic linkages to and alignment with other broad public health programs and initiatives to help accomplish the substantive work of syphilis control and to promote sustained advocacy and public support for syphilis prevention efforts. Although efforts within and across these tiers of syphilis prevention activities should and do reinforce each other, they also compete for resources: Tier 2 activities have been particularly in need of enhancement for many years. Tier 3 activities are especially important in the mid-1990s because, after the major epidemic of the late 1980s, syphilis rates are on the decline, making it urgent but difficult to sustain prevention efforts.