The human neurodegenerative diseases, including motor neuron disease and Alzheimer's disease (AD), are characterized by a selective involvement of certain regions of the brain/spinal cord and selected populations of neurons. Sporadic amyotrophic lateral sclerosis (ALS) is an age-associated disease with cytoskeletal abnormalities and death of motor neurons; familial ALS (FALS), an autosomal dominant disease linked to mutations in superoxide dismutase 1 (SOD1), is manifested by inclusions and degeneration of motor neurons. Autosomal dominant familial AD (FAD), linked to mutations in presenilin (PS1 and PS2) genes or the amyloid precursor protein (APP) gene, shows brain abnormalities (e.g., neurofibrillary tangles, deposits of .-amyloid A., and death of subsets of neurons) similar to those that occur in sporadic AD, the risk of which is enhanced by the presence of one or two copies of apolipoprotein E4 (apoE4) alleles. To examine the mechanisms of these diseases, investigators have used a variety of animal models, including experimentally produced, spontaneously occurring, or genetically engineered models of disease. Studies of models of degeneration of motor neurons (axotomy) and cytoskeletal abnormalities seen in motor neuron disease (i.e., axonopathy induced by .,.'-iminodipropionitrile (IDPN), hereditary canine spinal muscular atrophy (HCSMA), and neurofilament NF transgenic Tg mice) have demonstrated that NF-filled swellings of axons are related to alterations in the biology of NF transport. Tg mice with SOD1 mutations, which develop the clinical features of FALS, show selective degeneration of motor neurons, which is attributed to the acquisition of toxic properties by mutant SOD1. Models of AD include: aged monkeys that show both cognitive/memory deficits and cellular abnormalities (amyloid deposition/cytoskeletal abnormalities of neurons) in cortex and hippocampus; and Tg mice that express mutant human FAD-linked genes (i.e., APP and PS1) and show increased levels of A.42, amyloid deposits, dystrophic neurites, and local responses of astrocytes and microglia. This review discusses the behavioral/neuropathological features of AD, the results of investigations of mechanisms of disease in model systems, and potential utility of some of these models for testing new therapies.