Chlamydia is the most commonly reported bacterial disease in the United States, and remains the leading bacterial cause of sexually transmitted infection, responsible for approximately 90 million new STI cases annually worldwide. Of particular concern is that infections with C. trachomatis can lead to severe medical complications in women, such as pelvic inflammatory disease and ectopic pregnancy. Alarmingly, there remain fundamental gaps in our understanding of Chlamydia pathogenesis in vivo, for example their natural course of infection in humans and why protective immunity is not established. To help address these questions, our laboratory has been interested in determining how Chlamydia disseminate within the host. Our original discoveries elucidated the mechanisms by which chlamydiae exit host cells in vitro. Surprisingly, Chlamydia possess two mechanisms for cellular escape that are mutually exclusive: ( i) Extrusion, a packaged release of Chlamydia in which the vacuole pinches off and exits the cell within a membrane-encased compartment; this leaves the original host cell intact, often with a residual chlamydial inclusion. ( ii) Lysis, a destructive process that is mediated by proteases and the sequential rupture of vacuole, nuclear and plasma membranes, culminating in the release of free bacteria. The maintenance of two discrete exit mechanisms underscores the fundamental importance of this process for intracellular pathogens such as Chlamydia. Extrusions are novel pathogenic structures that we hypothesise confer unique means of interacting with the host’s innate immune system, enabling immune evasion and promoting tissue dissemination. To this end, we have recently illuminated key characteristics of chlamydial extrusions that allow direct infection of new cells and their engulfment by professional phagocytes. Bacteria within phagocytosed extrusions are protected from macrophage killing mechanisms for at least 8 h. These results have important implications for Chlamydia pathogenesis in vivo, including dissemination, transmission and the elicitation of immune responses.