ONLINE COVER To promote and maintain neural connectivity, endosomes carry survival signals to the nuclei of nerve cells. But how do endosomes find their way over the long distances from the synapse (the space between nerve cells) to the nucleus? Using microfluidic devices and mice, Scaramuzzino et al. found that the endosomes (blue spheres), which are tethered to molecular motors walking along the microtubule network (green rods), carry a calcium-sensing molecule on their surface that provides an internal navigation system to guide them toward the nucleus (orange globe). This work may increase understanding of several neurodegenerative diseases.