Neural crest (NC) migration has been studied extensively to understand long-range collective and directional migration. Many of the molecular players involved in this process have been identified, including semaphorins. Semaphorins are migration repellents that prevent invasion of NC cells into surrounding tissues by reducing the activity of the small GTPase Rac1 and, consequently, cytoskeletal dynamics. Despite the inhibitory role of semaphorins, NC migration occurs normally in their absence, indicating that additional mechanisms must regulate migration. Now, Brenda Canales Coutiño and Roberto Mayor find that the mechanosensitive ion channel Piezo1 is involved in NC migration in Xenopus. They observe that upon inhibition of Piezo1, either using morpholinos or a chemical inhibitor, NC cells migrate faster in vitro owing to an increase in both focal adhesion dynamics and Rac1 activity. Likewise, upon Piezo1 inhibition in vivo, NC migration is abnormal, with shorter NC streams and invasion of areas normally regulated by semaphorin signals. The authors report that loss of Piezo1 is sufficient to overcome the inhibitory effect of semaphorin on Rac1. Together, these data describe how effective NC migration is dependent on regulation of Rac1 activity by both chemical and mechanical signals.