In Drosophila, the combination of cell adhesion molecules (CAMs) expressed on axons has long been known to play a major role in the control of axon targeting, in particular of small subsets of motor axons to subsets of body wall muscles (Goodman, 1996). However, in vertebrates, the axon guidance defects revealed by the analysis of brain development in several CAM knockout mice were rather mild compared to the predicted models, therefore suggesting that, in vertebrates, CAM function might be highly redundant or rather limited and associated to additional guidance factors. A novel study by Williams et al. (2006) shows that this conclusion is obsolete and that, as originally proposed, CAMs have an essential role in axon guidance in the vertebrate central nervous system (CNS) as in invertebrates by selectively promoting the outgrowth of subsets of axons.