Calcium arising through release from intracellular stores and from influx across the plasma membrane is essential for signalling by specific guidance cues and by factors that inhibit axon regeneration. The mediators of calcium influx in these cases are largely unknown. Transient receptor potential channels (TRPCs) belong to a superfamily of Ca2+-permeable, receptor-operated channels that have important roles in sensing and responding to changes in the local environment. Here we report that XTRPC1, a Xenopus homolog of mammalian TRPC1, is required for proper growth cone turning responses of Xenopus spinal neurons to microscopic gradients of netrin-1, brain-derived neurotrophic factor and myelin-associated glycoprotein, but not to semaphorin 3A. Furthermore, XTRPC1 is required for midline guidance of axons of commissural interneurons in the developing Xenopus spinal cord. Thus, members of the TRPC family may serve as a key mediator for the Ca2+ influx that regulates axon guidance during development and inhibits axon regeneration in adulthood.