Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. The author initially summarizes the principal features of human ALS neuropathology, and subsequently describes in detail ALS animal models mainly from the viewpoint of pathological similarities and differences. ALS animal models in this review include strains of rodents that are transgenic for superoxide dismutase 1 (SOD1), ALS2 knockout mice, and mice that are transgenic for cytoskeletal abnormalities. Although the neuropathological results obtained from human ALS autopsy cases are valuable and important, almost all of such cases represent only the terminal stage. This makes it difficult to clarify how and why ALS motor neurons are impaired at each clinical stage from disease onset to death, and as a consequence, human autopsy cases alone yield little insight into potential therapies for ALS. Although ALS animal models cannot replicate human ALS, in order to compensate for the shortcomings of studies using human ALS autopsy samples, researchers must inevitably rely on ALS animal models that can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy. Of course, human ALS and all ALS animal models share one most important similarity in that both exhibit motor neuron degeneration/death. This important point of similarity has shed much light on the pathomechanisms of the motor neuron degeneration/death at the cellular and molecular levels that would not have been appreciated if only human ALS autopsy samples had been available. On the basis of the aspects covered in this review, it can be concluded that ALS animal models can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy only in combination with detailed neuropathological data obtained from human ALS autopsy cases.