Neurofilament proteins are continuously modified during their lifetime by a succession of protein kinases and phosphatases. Site-specific phosphorylation or dephosphorylation within different polypeptide domains of each neurofilament subunit is now believed to regulate such behaviors of neurofilaments as subunit polymerization and exchange, axonal transport, interactions with other cytoskeletal proteins and degradation. Local regulation of phosphorylation events could account for variations in the size, morphology and dynamics of the neurofilament network in different regions of the neuron. The apparent greater plasticity of the neurofilament network in regions like the perikaryon, initial segment and nodes along the axon may provide some insight into the vulnerability of these regions in neurofibrillary disease.