Syphilis rates are increasing in many parts of the world. HIV-infected persons, particularly men who have sex with men (MSM), have been affected disproportionately. In a recent study, 15% of patients attending New York City STD clinics who were diagnosed with syphilis subsequently became HIV-infected. Several questions about the optimal management of syphilis in HIV-infected persons remain unanswered and continue to elicit controversy, yet none of these are responsible for this persistent syndemic. There are, however, many questions whose answers may critically impact the control of these infections: What is the role of novel point-of-care syphilis tests? Is there a role for syphilis pre-exposure prophylaxis and male circumcision? How will PrEP impact the rates of syphilis? Seventy years following the introduction of a cure, and over 30 years after the discovery of HIV, syphilis continues to present formidable challenges to public health.