Syphilis, caused by a corkscrew-shaped bacterium, Treponema pallidum, is one of the most fascinating of all infections. The organism has a miniscule genome and is so fragile that it dies within hours outside of the host, yet it is capable of evading host defenses to persist for many decades within the host. Syphilis is known as “the great imitator” because its clinical manifestations can range from an ulcer or rash to blindness and insanity. In contrast, the infection can lie smoldering for many years, without any clinical evidence. How does T. pallidum cause the multiple stages of syphilis and still evade immune clearance? Is there a biological basis for determining which patients can be re-infected? Molecular studies involving the laboratory and the clinic have shed insights into pathogenic mechanisms involved in lesion development and clearance, induction of host responses, and immune evasion by T. pallidum. Our evolving knowledge about these issues will be discussed in the context of the natural history of syphilis infection.