Syphilis is a chronic sexually transmitted infection caused by Treponema pallidum subspecies pallidum. Its protean clinical presentations earned it the name of the 'Great Mimicker'. Understanding of disease pathogenesis and how host-pathogen interactions influence the course of disease have been compromised by the facts that the organism cannot be grown in vitro and, as an exclusively human pathogen, inferences made from animal models are of limited applicability. Many questions remain about how T. pallidum biology contributes to distinctive features of syphilis, such as its ability to persist in the presence of a brisk host response or its propensity for neuro-invasion and congenital transmission. In 1998, the genome of T. pallidum was sequenced. The organism has a relatively small genome, suggesting that it utilizes host biosynthesis to fulfil some of its metabolic needs. While biological functions are suggested for only about 55% of T. pallidum's 1041 open reading frames, even these relatively early studies offer important insights into syphilis pathogenesis. A family of repeat genes, the Tp genes, encode proteins homologous to the major sheath proteins of T. denticola. Antibodies to the TprK variable regions are protective in a rabbit model. With successive passage, increasing diversity is observed in the TprK V region genes. Antigenic variation through gene conversion has been hypothesized to be one mechanism of escaping immune surveillance, allowing for prolonged infection and persistence in the presence of a robust host response. Human and animal studies suggest that a Th1 response is elicited in primary syphilis. Progression to the secondary stage is accompanied by a shift to a Th2 response, allowing for incomplete clearance of the pathogen. In pregnancy, intense inflammatory responses and prostaglandins induced by fetal infection may be responsible for fetal death or pre-term delivery and severe growth retardation or other manifestations of congenital syphilis. Understanding of the molecular targets of these immune responses may facilitate the development of vaccines for syphilis.