Early syphilis therapy was a focus of intense research in the early 20th century with many and varied approaches being used. The development of penicillin and its efficacy in the treatment of syphilis transformed syphilis management for many with and at risk for infection. However, problems such as beta-lactam allergies and the desire for easily administered, alternate therapies have led to evaluation of multiple other drugs, with doxycycline currently recommended as the main alternative. Ceftriaxone and azithromycin have been shown to be effective, however, each has its own difficulties. Follow-up relies on serological testing, leading to concerns when these tests do not decline appropriately. Given concerns about the potential for increased risk for treatment failure, patients with HIV and pregnant women are of PTicular concern. © 2013 Informa UK Ltd.