Toxic gain of function affecting motoneurons and neuromuscular junctions would operate as a pathogenetic system of injury to neurofilaments and cytoskeleton of axons and neuronal cell bodies. Oxidative stress appears directly implicated in the development of a disease that evolves largely as loss of neurons in the anterior spinal horns of gray matter and as extensive loss of axons in the corticospinal tracts. The evolution of denervation atrophy of multiple groups of myofibers appears an integral component of this toxic gain of function mediated by oxidative stress and operating at least in part as also a primary site of disease involvement. It would appear that amyotrophic lateral sclerosis is one aspect of a whole series of possible outcomes of a diseased neuronal phenotype that evolves in terms of cytoskeletal and neurofilament pathobiology bridging aberrant axonal sprouting, synaptic loss and neuronal cell loss.