We have examined the relationship between mechanical injuries and the subsequent development of classic amyotrophic lateral sclerosis (ALS) through a critical review of the literature. Only prospective evaluation of a large cohort of trauma victims can provide an unbiased answer to this controversy. However, such an evaluation would be prohibitively expensive, and the results would not be available in our lifetime. The results of retrospective case-control studies are conflicting in part because of biases in the selection of patients and controls, poor definition of the nature and extent of the trauma and its chronological relationship to the onset of ALS, and a non-uniform approach to the collection of antecedent information. More rigorously designed studies show no association of ALS to antecedent trauma. The existing data thus do not suggest that mechanical trauma is a risk factor for ALS. Future case-control studies should conform to a standardized methodology. The critical analysis presented here of the research on the purported connection between mechanical injury and ALS may serve as a model for the evaluation of the role of trauma in other chronic diseases. Application of these methodological principles may bring increased scientific rigor to assessing the frequently litigated question of what constitutes a true trauma sequela.