Syphilis has changed the course of history. It is a sexually transmitted disease caused by spiral-shaped bacterium, Treponema pallidum. The disease has been known under many names during history, and has had a prominent role in history and literature for the last several hundred years. Since its recognition in 15th-century Europe as a new disease, syphilis has been the subject of great mystery and legends. Many believe that syphilis was brought to Europe by Columbus and his sailors, and, thereafter, many famous persons, such as political figures (King Charles VIII, Queen Mary I, Catherine the Great, Paul I, Vladimir Lenin), musicians and literary greats suffered from syphilis. Syphilis is a chronic, multistage disease with diverse and wide-ranging manifestations. Congenital syphilis is of particular concern, where the lack of prenatal testing and antibiotic treatment of infected pregnant women results in congenital infection of the fetus. Syphilis exists even nowadays and according to the World Health Organization estimates, there are 12 million new cases of syphilis occurring each year. While syphilis eradication seems a biologically plausible goal, the major political, cultural, and logistic difficulties involved make it unlikely. Regrettably, rather than becoming an infection of historical significance, syphilis continues to challenge researchers and clinicians in the era of HIV.