The efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts. Keywords Voltage-gated sodium channel Á Node of ranvier Á Axon–glial interactions Á Myelin Á Action potential propagation Á Neurological disease Abbreviations AP Action potential AIS Axon initial segment Na v Voltage-gated sodium channels K v Voltage-gated potassium channels PNS Peripheral nervous system CNS Central nervous system CAM Cell-adhesion molecule ECM Extracellular matrix Nfasc Neurofascin GPI Glycosyl phosphatidylinositol MS Multiple sclerosis GBS Guillain–Barré syndrome EAE Experimental autoimmune encephalomyelitis