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Chlamydial interactions with host cells rely on chlamydia-secreted proteins, including preexisting and newly synthesized proteins. The preexisting proteins released from EBs participate in both chlamydial entry and intracellular survival at the early stage while the newly synthesized proteins secreted from RBs can both manipulate host cell signaling pathways and promote chlamydial reinfection. Despite the significant progresses made in the past decade, the precise mechanisms on what and how chlamydia-secreted proteins interact with host cells remain largely unknown, and will therefore still represent major research directions of the chlamydial field in the foreseeable future. Development of more effective methodologies will aid in discovery of new secretion molecules and novel mechanisms utilized in chlamydial interactions with host cells. The continuing accumulation of knowledge on chlamydia-secreted proteins and their mechanism of action may lead to discovery of novel prevention and therapeutic reagents for preventing and controlling chlamydial infection and pathologies.