When first identified, neural cell adhesion molecules (neural CAMs) were thought to act simply by providing cell surfaces with differential adhesion properties. In the decades following the identification of the first neural CAMs, it has been realized that these proteins are actually involved in very complex processes such as axon guidance, neuronal migration, neurite outgrowth and fasciculation, target selection, synapse formation, plasticity and more recently, the maintenance of the integrity of myelinated fibers. In this review we will summarize work relating to glycosylphosphatidylinositol-anchored CAMs (GPI-CAMs) and will highlight expression/function issues, protein interactions and the role of the GPI in signaling.