How semaphorins stimulate plexins to regulate axon steering is an actively investigated question. Ventura and Pelicci discuss new evidence indicating that MICAL, a putative monoxygenase, transmits the signal from the receptor plexin to the actin cytoskeleton through a redox mechanism. MICAL could act either indirectly, causing a local increase in the concentration of reactive oxygen species (ROS), or directly, inducing redox changes in downstream effectors, such as actin and members of the Rho and Rac family of guanosine triphosphatases. Because semaphorin-plexin signaling plays a role in a number of clinically relevant settings, including recovery from spinal cord trauma, regulation of the immune system, and cancer metastasis, these findings could have important therapeutic implications.