In this Review, Stelzner, Vollmuth and Rudel summarize current knowledge of Chlamydia trachomatis intracellular replication, its metabolism within the host cell and how it defends against host cell autonomous and innate immune responses, as well as its transition to a persistence state. In recent years, substantial progress has been made in the understanding of the intracellular lifestyle of Chlamydia trachomatis and how the bacteria establish themselves in the human host. As an obligate intracellular pathogenic bacterium with a strongly reduced coding capacity, C. trachomatis depends on the provision of nutrients from the host cell. In this Review, we summarize the current understanding of how C. trachomatis establishes its intracellular replication niche, how its metabolism functions in the host cell, how it can defend itself against the cell autonomous and innate immune response and how it overcomes adverse situations through the transition to a persistent state. In particular, we focus on those processes for which a mechanistic understanding has been achieved.