Shigella is a causative agent of bacillary dysentery in humans. The ability of Shigella to disseminate in the intestinal epithelium is crucial for disease establishment. This process of cell-to-cell spread involves actin-based motility, which allows movement of Shigella through the cytoplasm, and the ability of Shigella to form filopodia-like membrane protrusions that are engulfed by adjacent cells. Compared to the process of Shigella actin tail assembly, which requires recruitment and activation of host actin modulators such as N-WASP and Arp2/3, the mechanism of how Shigella moves from an infected cell into neighboring cells and what host factors are involved remain poorly characterized. In this dissertation, I investigate whether members of the Ena/VASP family, as key actin regulators, or Inverse-BAR (I-BAR) family proteins, as coordinators of membrane curvature and actin dynamics, are required in dissemination of S. flexneri in a cell monolayer. Ena/VASP family proteins regulate cell migration, adhesion, shape, and cell-cell interaction. The members of the family include Vasodilator-Stimulated Phosphoprotein (VASP), Ena-VASP-like (Evl), and Mammalian enabled (Mena). We have previously shown that Mena, despite its localization to the actin tail, has no role in S. flexneri actin-based motility. Here, I investigate the role of Mena, Evl, and VASP in S. flexneri dissemination. I determine that the presence of VASP or Evl restricts cell-to-cell spread of S. flexneri. I further show evidence that the conserved EVH1 domain and phosphorylation of VASP regulate the ability of Shigella to spread. I-BAR proteins, including IRSp53 and IRTKS, contain a conserved domain that directly binds to membrane lipids and induces convex membrane deformation. This unique property and the ability of these proteins to bind F-actin and actin modulators are necessary for the formation of actin pedestals by pathogenic E. coli and filopodia. Using cells with reduced levels of IRTKS or IRSp53, I examine the role of these proteins in cell-to-cell spread and show that neither IRTKS nor IRSp53 is required for S. flexneri spread. Collectively, these results advance our understanding of host proteins that participate in S. flexneri dissemination.