Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease which is a group of chronic progressive disorders characterized by the selective degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. About 90 % of the cases are sporadic, while the rest are familial (inherited). The two forms are clinically indistinguishable and the pathophysiological mechanisms leading to motor neuron death are unknown. This paper reviews five of the prevailing hypotheses for the development of ALS: (a) Mutations in the gene encoding Cu2+/Zn2+ superoxide dismutase (SOD1; an enzyme which is essential in the cellular defense against oxidative injury), (b) activation of cellular self destruction programs (programmed cell death), (c) retroviral viral infection, (d) mitochondrial degeneration, and (e) impaired control of glutamate receptor activation ("the glutamate hypothesis"). The latter is the only one which has resulted in clinical trials to find a cure for ALS. I review three of these trials in relation to the guidelines for the design an implementation of clinical trials in ALS put forward by The World Federation of Neurology, committee of research.