Several mechanisms have been proposed to account for the progressive motor neurone death evident in amyotrophic lateral sclerosis. These include oxidative stress, neurofilament damage, mitochondrial abnormalities, glutamate-mediated excitotoxicity and altered responses to hypoxia. Current quests for therapies involve studying combinations of agents that act by various mechanisms and evaluating stem-cell therapies in model systems. High-throughput cell-culture screening systems are also being developed. The goal for therapy is to define agents that clearly prevent progression of, and it is hoped even reverse, motor neurone loss.