The role of cell adhesion molecules (CAMs) in oligodendrocyte–axon contact and myelination is not well understood. Overexpression of the membrane-bound extracellular domain of the CAM CADM4 (CADM4-ED) in cultured oligodendrocytes resulted in an increased number of axoglial contact sites but reduced myelin maturation compared with controls. Overexpression of CADM4-ED in mice resulted in hypomyelination of axons and inappropriate myelination of soma. These results indicate a key role for axoglial CAMs in proper myelin targeting and maturation.