Concerning the mechanism(s) of disease underlying amyotrophic lateral sclerosis (ALS), transgenic mouse models have provided (i) a detailed look at the pathogenic progression of disease, (ii) a tool for testing hypotheses concerning the mechanism of neuronal death, and (iii) a host appropriate for testing therapeutic strategies. Thus far, these efforts have proved that mutation in a neurofilament subunit can cause progressive disease displaying both selective motor neuron death and aberrant neurofilament accumulation similar to that reported in human disease. Additional mice expressing point mutations in the cytoplasmic enzyme superoxide dismutase (SOD1), the only known cause of ALS, have proved that disease arises from a toxic property of the mutant enzyme rather than loss of enzymatic activity.