Recognition of the early symptoms and signs in amyotrophic lateral sclerosis, exclusion of alternative diagnoses, and referral to a tertiary center can have a significant positive impact on the lives of patients and their caregivers. This article provides the most current amyotrophic lateral sclerosis criteria, as well as helpful clinical clues to the diagnosis. An approach to laboratory testing, electrodiagnostic testing, and imaging to exclude diseases that mimic ALS also are discussed, as are atypical presentations that can confound timely diagnosis.