There are an estimated 10.6 million incident cases of syphilis worldwide each year. We highlight some persistent challenges and emerging trends in the clinical management of syphilis with a particular focus on therapy, serology, diagnostics, and prevention. Decades after the introduction of penicillin, the optimal management of early syphilis continues to be a controversial topic, particularly in the setting of HIV co-infection. Similarly, the need for routine lumbar puncture in HIV co-infected asymptomatic persons is an unanswered question. Despite advances in both automation and point-of-care diagnostics, we continue to rely on indirect measures of disease activity to manage this infection. As syphilis rates in some populations continue to rise, novel and effective prevention strategies are needed.