Migration of primordial germ cells (PGCs) to the gonad after they are specified during gastrulation provides a model system for exploring control of directed cell migration. In the zebrafish, such migration is regulated by the chemokine Sdf-1A, which is secreted by somatic tissues and influences germ cells through the G protein-coupled receptor CXCR4b. Dumstrei et al. dissected the signaling systems that permit this receptor to specify proper migration of PGCs. Specific expression of pertussis toxin (an inhibitor of the Gi family of G proteins) in germ cells resulted in embryos in which PGCs did not arrive at their proper position in the presumptive gonadal region. Time-lapse microscopy of germ cells tagged with green fluorescent protein (GFP) showed that the cells were viable and motile but were not properly attracted to cells that secreted the Sdf-1A chemokine. Inhibition of signaling through the phosphoinositide 3-kinase (PI3K) pathway through expression of a dominant-negative form of PI3K in the germ cells resulted in cells that often still found their way to the gonad. However, the cells migrated more slowly and had abnormal morphology and stability of filopodia. In other systems of chemotaxis, 3-phosphorylated phosphoinositides are concentrated at the leading edge of cells and recruit proteins containing PH (pleckstrin homology) domains. However, other mechanisms appear to account for the polarized signaling in germ cells, because microscopy to follow the localization of GFP-tagged PH domain peptides revealed no variation in the amount of these phosphoinositides in the plasma membrane. The authors conclude that signaling through Gi proteins is critical for proper directional migration and that the PI3K pathway has essential roles for general motility of the germ cells.