The challenge of identifying patients at the earliest stage of disease has highlighted the role of subtle markers of clinical pathology. Electrophysiological changes usually precede evidence of clinical weakness and have, therefore, been implicated. Specifically, the onset of fasciculations, particularly those widespread in distribution, in the absence of fibrillation potentials, have been suggested as an early indicator of motor neuron disease. Several cases will be presented here to highlight instances where diffuse fasciculations were not enough to accurately implicate the current diagnostic criteria for amyotrophic lateral sclerosis (ALS). In two instances, alternative diagnoses were eventually supported. If the purpose of early diagnosis is to lead to early treatment with experimental therapy, we must be certain that we study as homogenous a population of patients as possible. Fasciculations by themselves are not enough to implicate early diagnosis; disease progression is probably the single most important historical characteristic for diagnosis. Signs of active denervation (i.e. fibrillation potentials) are critical. Chronic weakness should be proportional to either atrophy or upper motor neuron signs in the affected muscle. This should be true for both early and late recognition of the disease.