Amyotrophic lateral sclerosis (ALS) is typically regarded as a sporadic neurodegenerative disorder that results in a catastrophic failure of the motor system, with characteristically variable involvement of upper and lower motor neuronal populations. A wide range of evidence from clinical, histological, genetic, neurophysiological, neuroimaging and neuropsychological studies, suggests that a loss of central nervous system inhibitory neuronal influence is a contributing factor in ALS pathogenesis. This loss of inhibitory function points intuitively to an 'interneuronopathy', with natural differences in cortical and spinal inhibitory networks reflected in the hitherto unexplained variable compartmentalization of pathology within upper and lower motor neuron populations. An excitotoxic final common pathway might then result from unopposed glutamatergic activity. If correct, therapies aimed specifically at supporting interneuronal function may provide a novel therapeutic strategy.