Conduction block is an important functional consequence of demyelination whereby nervous transmission is abolished. Its mechanism has been discussed with respect to the loss of insulation due to disruption of myelin. Recent development of threshold tracking techniques, which enabled noninvasive assessment of axonal membrane potentials and ion channels, has provided evidence that axonal excitability changes significantly and contributes to conduction failure. This view, based upon axo-glial interaction, clarifies the mechanism of muscle fatigue and fasciculation associated with peripheral demyelination and possibly explains selective motor involvement in multifocal motor neuropathy.