Mutations in the human genes for the adhesion molecules Po, L1, and merosin cause severe abnormalities in nervous system development. Po and merosin are required for normal myelination in the nervous system, and L1 is essential for development of major axon pathways such as the corticospinal tract and corpus callosum. While mutations that lead to a loss of the adhesive function of these molecules produce severe phenotypes, mutations that disrupt intracellular signals or intracellular interactions are also deleterious. Geneticists have found that more than one clinical syndrome can be caused by mutations in each of these adhesion molecules, confirming that these proteins are multifunctional. This review focuses on identifying common mechanisms by which mutations in adhesion molecules alter neural development.