TGFbeta is a potent immune deviating agent, driving active forms of immune tolerance in peripheral tissues through effects on the induction and resolution of inflammatory responses and phenotype skewing in antigen-presenting cells and lymphocytes. The TGFbeta content of seminal plasma from human, rodent and livestock species is amongst the highest measured in biological fluids. The seminal vesicle gland is the principal source of TGFbeta in the semen of mice, where its synthesis is regulated by testosterone. At insemination, seminal TGFbeta is deposited in the female tract and is activated by acidic vaginal pH, enzymes of male or female tract origin, or through cleavage-independent processes involving conformational change after interaction with epithelial cell docking proteins. Seminal TGFbeta has been shown to be a principal stimulating agent in the post-coital inflammatory response, and is likely to be essential for induction of immune tolerance to seminal antigens. As well as preventing aberrant immunity to spermatozoa, these events are implicated in priming an appropriate female immune response to embryo implantation, since many seminal antigens are shared by the conceptus. The cascade of immunological events elicited by seminal TGFbeta may therefore explain epidemiological observations linking acute and cumulative exposure to semen with successful placental development and pregnancy outcome. Depending on whether the female tract has evolved mechanisms to discriminate seminal antigens from opportunistic pathogens, there may be a detrimental cost of seminal TGFbeta in inhibiting protective immunity to agents of sexually transmitted disease including HIV. A better understanding of the significance and role of TGFbeta in semen will facilitate development of novel therapies for immune-based infertility disorders.