The actin-related protein 2/3 (ARP2/3) complex nucleates branched actin filaments and underlies the formation of lamellipodia — sheet-like protrusions found at the leading edge of migrating cells. By generating a mouse embryonic fibroblast cell line depleted of ARP2/3, Wu et al. show that ARP2/3 and lamellipodia are essential for migration on surfaces coated with extracellular matrix (ECM) proteins (haptotaxis), but they are dispensable for chemotaxis (migration guided by soluble factors). ARP2/3-depleted cells did not form lamellipodia, had altered focal adhesion dynamics and failed to migrate on various ECM gradients. However, ARP2/3-depleted cells formed more filopodial protrusions and, surprisingly, could still respond to a soluble platelet-derived growth factor gradient, albeit more slowly. The requirement for lamellipodia in haptotaxis but not in chemotaxis suggests that cells use distinct mechanisms to respond to these different directional cues.