Coxiella burnetii, the causative agent of human Q fever, is an intracellular pathogen that replicates in a lysosome-derived vacuole. The molecular mechanisms used by this bacterium to create this unique replicative niche remain largely unknown. Advances in axenic culture and genetic manipulation of this organism have allowed us to conduct a large scale visual screen of a C. burnetii transposon-insertion mutant library to identify genes required for biogenesis of a mature Coxiella-containing vacuole (CCV). This study confirmed our earlier findings that the Dot/Icm Type IV Secretion System is essential for intracellular replication of C. burnetii and also allowed identification of individual Dot/Icm effectors that are required for development of the CCV. Disruption of the gene encoding the Dot/Icm effector Cig57 rendered the bacteria significantly compromised for intracellular replication. This intracellular replication defect displayed by the cig57 mutant was complemented upon introduction of cig57 on a plasmid and our further studies indicate this is linked to the interaction between Cig57 and clathrin coated vesicles. Furthermore, we identified the Dot/Icm effector Cig2 as being required for homotypic fusion of CCVs. Importantly, we demonstrate that interfering with host autophagy during infection by wild type C. burnetii resulted in a multi-vacuolar phenotype similar to that displayed by the cig2 mutant. Cig2 does not upregulate autophagy on a global scale however this effector is important for the robust fusion of CCVs with autophagosomes. These studies indicate aspects of eukaryotic cell biology that are commandeered by C. burnetii to create a unique replicative niche.