Amyotrophic lateral sclerosis (ALS) is an incurable disease that arises from the progressive loss of motoneurons. Even when caused by a single gene defect, as in the case of mutations in the enzyme Cu– Zn superoxide dismutase (SOD1), ALS is the result of a complex cascade that involves crosstalk among moto-neurons, glia and muscles, and evolves through the action of converging toxic mechanisms. Transgenic rodents that express human mutant SOD1 and develop a progressive paralytic disease are widely used to screen potential therapeutics. Treatments that interfere with a specific event in the neurotoxic cascade have been reported to produce a modest increase in rodent lifespan. Multi-intervention approaches, including novel methods to intercept the damage and to deliver molecules to vulnerable cells, have recently been shown to be more effective. Thus, new avenues for promising therapeutic approaches can be derived from multidrug treatments and/or the delivery of growth factors by viral vectors, in combination with exercise and/or diet regimens. Amyotrophic lateral sclerosis: an elusive pathology Amyotrophic lateral sclerosis (ALS) is a fatal disorder that is characterized by the selective loss of upper and lower motoneurons and by progressive muscle atrophy. ALS is one of the most common neurodegenerative disorders, with a prevalence of between four and six per 100 000, and it occurs in sporadic (sALS) and familial (fALS) forms. The best-known cause of ALS, which is responsible for 1/5 of the cases of fALS, is a mutation in the gene that encodes the enzyme Cu–Zn superoxide dismutase (SOD1), a well-characterized enzyme that is abundant in the cytoplasm and mitochondria of virtually every cell type. Almost 120 different SOD1 point mutations have been reported in families with ALS (http://www.alsod.org) but the mechanism (or mechanisms) through which mutant SOD1 (mSOD1) enzymes produce the pathological pheno-type is still debated [1,2]. In 2001, Turner et al. [3] listed w50 different medications that have been tested for the treatment of ALS since 1941, all but one of which had no effect on patient survival. More trials have been conducted since 2001, although they have also been ineffective (an