The laboratory diagnosis of syphilis remains a challenge to physicians. The organism cannot be subcultured and dark‐field microscopy requires a skilled operator. Current routine assays rely on serological‐based techniques, which cannot distinguish syphilis from other treponemal infections such as yaws and pinta. False‐positive and false‐negative results can occur, as well as difficulties between differentiating between acute and chronic infection. Concomitant infection with human immunodeficiency virus (HIV) can also skew results. Molecular analysis with polymerase chain reaction (PCR) is promising but is still in its infancy and standardisation is required. Therefore in order to diagnose syphilis correlation with the history and clinical examination findings remain of paramount importance.

Key Concepts:

• Models of the cyclical epidemics of syphilis, which have been proposed and the factors that influence their periodicity and size of recurrence.
  
• Comparison with the Treponema species that infect man with those from primates points to the origin of the disease, whereas study of their molecular structure throws light on treponemal biology.
  
• The role of serological tests in the diagnosis of syphilis is analysed. Rapid screening tests are contrasted with more sophisticated laboratory tests. An example of the latter is the place of confirmatory tests.
  
• The reasons for the gradual introduction of molecular tests like PCR into the diagnostic armoury and their current shortcomings are evaluated.
  
• The practical difficulties of manufacturing and introducing a syphilis ‘vaccine’ are addressed, despite the theoretical and experimental support for this approach.