A direct role of aberrant neurofilament accumulation in the etiology of human motor neuron diseases, including amyotrophic lateral sclerosis, is suggested by the presence of abnormal accumulations of neurofilaments as an early hallmark of the pathogenic process. Furthermore, forcing increased expression of neurofilament subunits in transgenic mouse models leads to motor neuron dysfunction, albeit without the widespread motor neuron death typical of human disease. We now show that accumulation of a modest level of a point mutant in the smallest neurofilament subunit (NF-L) causes massive, selective degeneration of spinal motor neurons accompanied by abnormal accumulations of neurofilaments and severe neurogenic atrophy of skeletal muscles. As in human disease, sensory neurons show only a modest level of degenerative changes. Thus, neurofilament mutations can cause selective motor neuron death, and neurofilamentous abnormalities may be a common toxic intermediate that significantly contributes to the motor neuron death in human disease.