Axonal pathfinding occurs through detection of environmental cues by cytoskeletal machinery that is responsible for growth cone migration. The cycle of filopodial and lamellipodial protrusion, adhesion, and generation of tensions to advance a growth cone result from concerted actions of ABPs to regulate actin filament polymerization, assembly into networks and bundles, and production of tension to move the growth cone and its contents. The direction of neurite elongation is controlled by forward movement of microtubules in growth cones, which is pioneered by the advance of microtubules into P domain of the leading margin. Actin filaments both promote and impede this advance of microtubules in several ways. This cytoskeletal machinery is controlled by major signaling mechanisms. To understand growth cone guidance we must reveal the spatial and temporal changes generated in [Ca++]i, phospholipids, and protein phosphorylation and dephosphorylation, and then identify the ABPs and MAPs that are their targets.