At the level of the herd (nations), the epidemic of Chlamydia trachomatis genital tract infections has not been controlled despite medical interventions including screening, treatment and partner management programs. However, at the level of the individual it is clear that the host immune response of humans and animals is capable of clearing infection, or at least controlling it asymptomatically at a level below that detectable with current diagnostic assays. Aggressive chlamydia screening and treatment programs appear to be counterproductive for reducing the incidence of disease, likely due to a detrimental effect on herd immunity. The unintentional demonstration of herd immunity revealed by unsuccessful antibiotic-based public health strategies offers a hopeful glimpse into possibilities for future immunologic/vaccine-based interventions. A key to successful implementation of a vaccine-based strategy will be understanding the immunologic goal of vaccination, i.e. the parameters that define a protective host immune response. In this chapter, we will examine what is currently known about the immune response to genital chlamydial infections based on data from experimental animal models and limited human studies. © 2013 S. Karger AG, Basel.