Publisher Summary This chapter discusses the signaling through RHO GTPases in phagocytes. GTPases act as molecular switches by cycling between the GDP to the GTP-bound form. It is suggested that the interaction of opsonized particles with the Fc receptor on the surface of the phagocytes triggers a series of events leading to the engulfment of the particles. The process of phagocytosis is an actin-driven process that requires the reorganization of the actin cytoskeleton to complete the invagination and the budding of the phagosome from the plasma membrane. The link to the actin cytoskeleton strongly suggests that this process is regulated by Rho GTPases. Recent studies demonstrated that Rac and Cdc42 are required for the reorganization of the actin cytoskeleton in macrophages to form a-phagocytic cups which are essential for particle internalization during FcR mediated phagocytosis. In addition, inactivating Rho by C3 exoenzyme blocked Fcγ receptor-mediated phagocytosis. A most recent study reported two distinct mechanisms of phagocytosis: type I, mediated by the immunoglobilin receptor is controlled by Cdc42 and Rac, and type II, mediated by the complement receptor is regulated by Rho. The molecular effectors that are involved in this process are currently unknown.