Neurofilaments (NFs) are the major intermediate filaments in most mature neurons. Genetic approaches have now proven that NFs are an essential determinant for radial growth of axons. NF phosphorylation most probably plays an important role in this function. Further, forced over-expression of NF subunits in transgenic mice yields NF misaccumulation in motor neurons and, subsequently, causes motor neuron dysfunction. This has important implications for human motor neuron diseases because similar accumulations are nearly universally found in the early stages of many motor neuron disorders.