The hereditary motor and sensory neuropathies (also known as Charcot-Marie-Tooth disease or CMT) are characterized by a length-dependent loss of axonal integrity in the PNS, which leads to progressive muscle weakness and sensory deficits. The 'demyelinating' neuropathies (CMT disease types 1 and 4) are genetically heterogeneous, but their common feature is that the primary defect perturbs myelination. As we discuss in this Review, several new genes associated with CMT1 and CMT4 have recently been identified. The emerging view is that a range of different subcellular defects in Schwann cells can cause axonal loss, which represents the final common pathway of all CMT disease and is independent of demyelination. We propose that Schwann cells provide a first line of axonal neuroprotection. A better understanding of axon-glia interactions should open the way to therapeutic interventions for demyelinating neuropathies. Transgenic animal models have become essential for dissecting CMT disease mechanisms and exploring novel therapies.