Although amyotrophic lateral sclerosis (ALS) was first described in the 19th century by the French neurologist Charcot, the pathophysiological mechanisms underlying ALS development, and indeed the site of disease onset, remain unknown. Recently, there is emerging evidence of a complex interaction between molecular pathways and environmental factors, with cortical hyperexcitability proposed as an important mechanism in development of ALS via a dying forward anterograde process mediated by glutamate excitotoxicity. Utilizing novel threshold tracking cortical and peripheral nerve excitability techniques, our research has established that cortical hyperexcitability was an early feature in both sporadic and familial forms of ALS, correlating with peripheral biomarkers of axonal degeneration. Separately, our longitudinal cortical and peripheral nerve excitability studies undertaken in subjects expressing mutations in the superoxide dismutase-1 gene mutation [SOD-1] gene, the most frequent genetic cause of ALS, revealed that cortical hyperexcitability preceded the clinical onset of familial ALS by approximately four months, with corticomotoneuronal function initially preserved in asymptomatic SOD-1 mutation carriers. Of further relevance, studies in patients with ALS mimic disorders, such as Kennedy's disease, acquired neuromyotonia, hereditary motor neuronopathy with pyramidal features and motor neuropathies, confirmed that cortical hyperexcitability was a process specific to ALS. As such cortical hyperexcitability appears as a primary event in ALS, underlying the subsequent development of motor neuron degeneration. Establishing that cortical hyperexcitability is a primary event in ALS has both diagnostic and therapeutic significance. Specifically, these findings would enable earlier institution of therapies and a more definitive diagnosis which remains vital for recruitment into future trials. As a result of this body of work, novel pathophysiological insights have been developed which in turn may result in development of new therapeutic strategies in ALS