Myelinated axons are highly differentiated in the vicinity of the node of Ranvier, both structurally and with respect to ion channel distribution. Evidence is reviewed showing that axonal differentiation depends upon two distinct types of interaction between glial cells and the axolemma, one at the node itself, with astrocyte processes, and the second, more extensive one, in the paranodal region, with oligodendrocyte processes. In the peripheral nervous system, Schwann cells fulfill both roles. Glial or Schwann cell abnormalities, due to genetic deficiencies, diseases or experimental procedures, result in corresponding abnormalities in the axolemma and can have devastating effects on nerve fiber function. An example, the myelin-deficient mutant rat, is presented, and the defects underlying the profound and ultimately lethal neurological abnormalities seen in this mutant are discussed in relation to abnormalities in its axoglial interactions.