This review summarizes current evidence suggesting that the pathogenetic basis of giant axonal neuropathies induced by neurotoxic chemicals involves a direct chemical modification of neurofilaments (NF) and/or related cytoskeletal proteins. Chemical modification of NF is believed to disrupt the normal cytoskeletal organization, which results in an alteration in NF transport rate and accumulation of NF at prenodal sites along the axon. The exact location at which axonal enlargements occur appears to be a continuous function, dependent on both the structure and dosage schedule of the chemical toxin. A unified hypothesis for the neuropathologic effect of the diverse spectrum of toxic chemicals known to induce giant axonopathies is presented, based on recently published data on the structure of NF protein. Neurotoxic chemicals are believed to alter the charge balance of highly ionic domains of NF proteins which are thought to enter into intermolecular coulombic interactions in forming the supramolecular cytoskeletal framework.