Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron degeneration, skeletal muscle atrophy, paralysis and death. The identification of mutations in Cu,Zn superoxide dismutase (SOD1) as a genetic cause of this disease has led to the creation of a number of in-vitro and in-vivo models. Experiments have been carried out in these model systems to address fundamental questions related to the disease: (1) what is the nature of toxicity of the mutated SOD1? (2) what are the cellular targets and pathways that lead to neuronal degeneration? (3) what makes motoneurons particularly vulnerable to the toxicity of the mutant enzyme? and (4) are there effective treatments for ALS based on current hypotheses regarding the disease mechanism? Current research on these questions is reviewed.