Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner.