Despite over a century of clinical experience in diagnosing and managing patients with syphilis, many thorny clinical questions remain unanswered. We focus on several areas of uncertainty for the clinician: the role of serologic tests in diagnosing syphilis and assessing syphilis treatment responses, and the risk of neurosyphilis and ocular syphilis in patients with syphilis. We also address whether clinical approaches should differ in patients who are, and are not, infected with HIV. The current increases in syphilis rates in the United States and elsewhere underscore our urgent need to definitively address these issues.