Trichomonas vaginalis is a sexually transmitted obligate extracellular parasite that colonizes the human urogenital tract. Despite being of critical importance to the parasite's survival relatively little is known about the mechanisms employed by T. vaginalis to establish an infection and thrive within its host. Several studies have focused on the interaction of the parasite with host cells and extracellular matrix, identifying multiple suspected T. vaginalis adhesins. However, with the exception of its surface lipophosphoglycan, the evidence supporting a role in adhesion is indirect or controversial for many candidate molecules. The availability of the T. vaginalis genome sequence paved the way for genomic analyses to search for proteins possibly involved in host-parasite interactions. Several proteomic analyses have also provided insight into surface, soluble and secreted proteins that may be involved in Trichomonas pathogenesis. Although the accumulation of molecular data allows for a more rational approach towards identifying drug targets and vaccine candidates for this medically important parasite, a continued effort is required to advance our understanding of its biology. In the present chapter, we review the current status of research aimed at understanding T. vaginalis pathogenesis. Applied experimental approaches, an overview of significant conclusions drawn from this research and future challenges are discussed.