This article brings together evidence to support the hypothesis that acquired nucleic acid changes are the proximate causes, "triggers," or "initiators" of sporadic amyotrophic lateral sclerosis (ALS). Clinical features that support this hypothesis include focal onset and spread, and the individualized rate of progression. Clues from the epidemiology of sporadic ALS include the increase in its incidence with age, suggesting accrual of time-dependent changes, and the emergence of smoking, a known carcinogen, as its first "more likely than not" exogenous risk factor. The identification of any exogenous risk factor suggests that a large proportion of sporadic cases have a triggering mechanism susceptible to that factor. Ingestion of the products of cycad circinalis has been hypothesized to be implicated in causing Western Pacific ALS. Cycad contains both neurotoxic factors and carcinogens. The dissimilarity of Western Pacific ALS from neurotoxic diseases suggests a greater likelihood that the effects of DNA alkylation are its proximate cause.