Neurofilaments are a major component of the axonal cytoskeleton and their abnormal accumulation is a prominent feature of the cytopathology encountered in several neurodegenerative diseases. Thus, an attractive and widely held model of pathogenesis involves the participation of disrupted neurofilaments as a common toxic intermediate. Here, in direct contrast to this hypothesis, we show that two neurodegenerative disease models in the mouse, dystonia musculorum (dt) and a superoxide dismutase 1 (SOD1)-mediated form of human motor neuron disease (amyotrophic lateral sclerosis, ALS), progress with little or no abatement on a transgenic background in which neurofilaments are withheld from the axonal compartment. By specifically excluding a necessary role for axonal neurofilaments, our observations redefine the components of the pathogenic pathway leading to axon disruption in these two degenerative diseases.