Motoneurone disease (MND or amyotrophic lateral sclerosis) is a paralysing disease of unknown cause involving progressive, widespread muscle atrophy due to degeneration of spinal and other motoneurones and an accompanying loss of Betz cells in the motor cortex. A current hypothesis attributes the disease to the loss of a muscle-derived neurotrophic factor acting in concert with the normal age-related deterioration and loss of motoneurones. The roots of this hypothesis are traced through research based mainly on the developing neuromuscular system, and in particular on the age-related processes of natural motoneurone death during embryogenesis: the neonatal reduction of polyneuronal innervation and the age-dependent variations in motor nerve terminal sprouting in response to partial denervation. A consideration of the disease process itself in association with the review of earlier work provide the background for the present work which reexamines ultrastructurally the chromatolytic and later responses to axotomy and the muscle-dependent factors responsible for the reformation of the Nissl bodies.