Cancer-cell migration is accomplished by the formation of specific cellular protrusions termed lamellipodia and filopodia at the leading edge of the cell. Lamellipodia formation is induced by rearrangement of the actin cytoskeleton and is generally regulated by a small GTPase Rac1 and WAVE2, a member of the Wiskott-Aldrich syndrome protein (WASP) family verprolin-homologous protein (WAVE) family of actin cytoskeletal regulatory proteins. This review focuses on the mechanisms underlying the Rac1- and WAVE2-mediated induction of lamellipodia formation in invasive human breast cancer MDA-MB-231 cells in response to hepatocyte growth factor (HGF). Stimulation of the cells with HGF induces lamellipodia formation that is accompanied by dissociation of the IQ motif containing GTPase activating protein 1 (IQGAP1) and the motor protein kinesin from CLIP-170, one of the microtubule-binding proteins, which is constitutively associated with Rac1. The dissociation of IQGAP1 and kinesin from the Rac1-CLIP-170 complex depends on phosphatidylinositol 3-kinase (PI3K), an upstream signaling molecule of Rac1; this association is crucial for HGF-induced lamellipodia formation. Then, the dissociated IQGAP1 and kinesin are recruited to the preexisting WAVE2-IQGAP1-kinesin complex. Simultanously, Pak1, one of the downstream effectors of Rac1, which is constitutively associated with the WAVE2 protein complex, mediates the Rac1-dependent phosphorylation of tubulin-bound stathmin, a microtubule-destabilizing protein, and recruits it to microtubules that bear the WAVE2 protein complex via kinesin. Finally, the WAVE2 complex is transported by kinesin towards the growing ends of microtubules at the leading edge of the cell where lamellipodia are subsequently formed.