The genus Chlamydia currently comprises twelve species of obligate intracellular Gram-negative bacteria that infect a wide variety hosts. Primary infections are established at mucosal sites (genital tract, respiratory tract, digestive tract and the eye) and are often subclinical or asymptomatic. These infections can be self-limiting or they may lead to chlamydial persistence and disease. The factors that determine the outcome of primary infection at the individual level are not understood. However, it is known that disease progression is the result of inflammation leading to tissue damage that is often irreversible. The inability to separate protective immunity from damaging inflammation has hampered chlamydial vaccine development. To better understand the pathogenesis of ovine enzootic abortion (OEA) with a view to developing a next generation safe and effective vaccine, we have established in vitro and in vivo models of C. abortus infection. In vitro models include epithelial and myeloid cells that provide insight into innate responses to C. abortus infection. In vivo models include the unequivocal demonstration of C. abortus persistence in non-pregnant ewes and a challenge infection during pregnancy that informs on maternal immunity. These models reveal that IFN-γ is not only a strong correlate of immunological protection but is also a factor in chlamydial persistence. Our data suggest that the immunological 'signatures' of protection against C. abortus are complex and that the mechanisms and route of antigen delivery are major factors in determining the outcome of vaccination and infection.