Neurofilaments (NFs) are prominent components of large myelinated axons. Based on sequence homology and intron placement, the NF genes have been classified as type IV IFs along with alpha-internexin, which is also expressed in the nervous system. NFs may function as effector proteins subject to a complex regulatory cross-talk between neurons and myelinating Schwann cells or oligrodendrocytes. Mammalian neurofilaments are assembled from light (NF-L), mid-sized (NF-M), and heavy (NF-H) neurofilament proteins. NF-M is required if myelinated axons are to achieve maximal diameters and NF-M has been shown to regulate the level of NF-L. NF-M subunits mainly regulate axonal caliber by altering the level of NF-L and in turn the number of NFs in the axon. Results seem to explain as a perturbation of NF stoichiometry in which overexpression of NF-M leads to the formation of perikaryal NF inclusions in motor neurons and the depletion of NFs from axons. Overexpression of NF-M in combination with NF-L increased radial growth of axons, which suggests that NF-M or NF-H must coassemble into filaments with NF-L before they can affect the radial growth of axons. The immature form of NFs composed of NF-L and NF-M, might function in establishing the early neuronal phenotype and in maintaining neurite outgrowth.