Besides the free radical hypothesis raised by the identification of Superoxide Dismutase I mutations in a subset of familiar Amyotrophic Lateral Sclerosis (ALS) patients, three etiopathogenic hypotheses for sporadic ALS, namely autoimmune, neurofilament, and glutamate toxicity, have attracted interest in the last few years. The role of autoimmunity in ALS has been seriously questioned. The excitotoxic hypothesis for ALS spurred two clinical trials with riluzole. The results of both studies showed a modest benefit in prolonging survival that was statistically significant. Riluzole was the first drug made available for ALS patients. It began a new era in both basic and clinical research. Various human recombinant neurotrophic molecules (CNTF, BDNF, IGF-I) were administered to ALS patients. IGF-I slowed the progression of functional impairment in patients with ALS with no adverse effects. The recent demonstration of the specific viral echovirus 7 RNA sequences in the spinal cord of ALS patients refocused research on the viral hypothesis of the disease and antiviral drugs are ready to be used in clinical settings. New treatment strategies are today under study: intrathecal infusion with BDNF, intrathecal capsules for neurotrophic factor secretion or in vivo gene therapy using viral vectors. New research findings are, more than for other diseases, immediately transferred to clinical ground for the desperate need of a curative treatment of the patients affected by ALS.