In the absence of treatment, syphilis is a lifelong infection with clinically manifest stages that alternate with periods of latency. The primary and secondary stages of the disease are highly infectious in that the agent of syphilis, Treponema pallidum subsp. pallidum (T. pallidum), actively proliferates in the lesions that stigmatize early syphilis (such as the primary chancre, and the secondary mucosal lesions and skin rash). Within these lesions, however, the increasing bacterial burden elicits a robust immune response that culminates with the immune clearance of the great majority of the treponemes and allows spontaneous lesion resolution. Nonetheless, very few treponemes successfully evade the host's immune response and latently persist in the affected individual for decades. Eventually, in approximately one third of the patients, the disease reactivates leading to the dreaded manifestations of tertiary syphilis, such as insanity, blindness, paralysis, or death. How some T. pallidum cells can successfully evade the host defenses is a key question mark in syphilis pathogenesis. A variety of mechanisms were proposed over the last three decades, including residence of the pathogen within intracellular or immune privileged niches, or its ability to cloak its surface with host proteins or mucopolysaccharides to disguise as self and avoid immune recognition. Although not abandoned, the strength of the above theories was significantly lessened by the discovery of phase variation mechanisms for four hypothetical outer membrane proteins (OMPs) candidates encoded by the T. pallidum tpr (T. pallidum repeat) gene family, and the demonstration that the variable antigen TprK is involved in treponemal immune selection during experimental infection. Such findings strongly suggest a role for some tpr genes in immune evasion and persistence. After one century from the isolation of the first T. pallidum strain in 1912 by Nichols and Hough, progress to elucidate the molecular mechanisms behind T. pallidum's persistence is still hindered by the inability to grow in vitro or genetically manipulate T. pallidum, the pathogen's limited viability outside of a host, and an uncommonly fragile cellular ultrastructure. Despite such limitations, much evidence support that immune evasion by the syphilis spirochete is based on sophisticated molecular strategies whose investigation could significantly deepen our understanding of syphilis pathogenesis and also favor the identification of broadly protective vaccines.