In leukocytes responding to a chemoattractant, the cellular polarity is regulated by activities of small Rho guanosine triphosphatases (Rho GTPases) and the phosphoinositide 3-kinases (PI3Ks). In neutrophils, lipid products of PI3Ks regulate activation of Rho GTPases and are required for cell motility. They accumulate asymmetrically to the plasma membrane at the leading edge of polarized cells. Spatially regulating Rho GTPases and organizing the leading edge of the cell, PI3Ks and their lipid products could play pivotal roles in establishing leukocyte polarity, as compass molecules that tell the cell where to crawl.