The bacterial pathogen Legionella pneumophila is the causative agent of Legionnaires' disease, which is associated with intracellular replication of the bacteria in macrophages of the human innate immune system. L. pneumophila enters host cells through phagocytosis. Once inside the host cells L. pneumophila manipulates vesicular trafficking pathways and establishes Legionella-containing vacuoles (LCV) that serve two purposes: to provide a safe niche for intracellular bacterial replication and to prevent bacterial degradation by the host's bactericidal lysosomal compartments. pneumophila uses a type IV secretion system called L. "Intracellular multiplication/Defective for organelle trafficking" (Icm/Dot), a key virulence factor, to inject almost 300 secreted effector proteins into its host cells. The secreted effector proteins are believed to play important roles in LCV biogenesis and intracellular multiplication of L. pneumophila. Several of these effector proteins are capable of interacting with host phosphoinositides (PIs). However, there has been no report to date of a L. pneumophila-coded PI- metabolizing enzyme. Given the indispensable role of PIs in vesicle trafficking, the main goal of my research was to identify, characterize, and study the role of L. pneumophila PI phosphatases in exploiting host PIs and subverting host cell vesicular trafficking during infection. I was able to show that L. pneumophila encodes an effector protein that we named SidP, which functions as a PI-3-phosphatase specifically hydrolyzing PI(3)P and PI(3,5)P2 in vitro. The enzymatic activity of SidP rescues the growth phenotype of a yeast strain defective in PI(3)P phosphatase activity. My crystal structure of a SidP ortholog from Legionella longbeachae reveals that this unique PI-3-phosphatase is comprised of three distinct domains: a large catalytic domain, an appendage domain inserted into the N-terminal portion of the catalytic domain, and a C-terminal -helical domain. SidP has a small catalytic pocket that likely provides substrate specificity by limiting the accessibility of bulky PIs with multiple phosphate groups. A unique conformation of the conserved arginine residue in the catalytic motif of SidP and the presence of a hydrophobic loop that covers the catalytic motif may participate in regulating the activity of SidP. Together, my identification of a unique family of Legionella PI phosphatases highlights a common scheme of exploiting host PI lipids in intracellular bacterial pathogen infections.