Whereas most cells in adult tissues are fixed in place by cell junctions, leukocytes are motile and able to migrate actively through the walls of blood vessels into surrounding tissues. The actin cytoskeleton of these cells plays a central role in locomotion, phagocytosis, and the regulation of cell shape that are crucial elements of neutrophil and monocyte/macrophage function. This review will concentrate on how macrophages in particular control the actin cytoskeleton to generate cell movement and the shape changes required for chemotaxis. It has recently become evident that a complex of seven proteins known as the Arp2/3 complex regulates the assembly of new actin filament networks at the leading front of moving cells. Proteins of the Wiskott-Aldrich Syndrome Protein (WASP) family bind directly to the Arp2/3 complex and stimulate its ability to promote the nucleation of new actin filaments. Upstream of the WASP family proteins, receptor tyrosine kinases, G-protein-coupled receptors, phosphoinositide-3-OH kinase (PI 3-kinase), and the Rho family of GTPases receive and transduce the signals that lead to actin nucleation through WASP-Arp2/3 action. Although many gaps remain in our understanding, we are now in a position to consider completing signaling pathways that are initiated from outside the cell to the actin rearrangements that drive cell motility and chemotaxis.