Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder 
characterised by loss of motor neurons. The cause of disease is unknown other 
than in the rare cases of familial disease arising from mutations in the 
superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - 
including oxidative stress, excitotoxicity, mitochondrial dysfunction and 
abnormal protein aggregation - based on studies of human post mortem tissue, 
research on animal models, and in vitro work. Here we review the evidence for 
the main pathogenic mechanisms and outline how they might interact to cause 
motor neuron death. Clinical trials have as yet failed to identify any truly 
effective therapies in ALS, with only riluzole providing a modest improvement in 
survival. Ongoing trials are exploring the value of antiglutamatergic agents, 
including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, 
mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective 
therapy will involve combinations of agents acting on different mechanisms. Gene 
therapy with neurotrophic factors will soon be in clinical trials, while work on 
stem cell therapy remains preclinical. In addition to finding effective 
therapies, research also needs to identify early disease markers because therapy 
is likely to be of most benefit when given early in the course of disease.