The spectrum of diseases that can affect a patient's strength is extraordinarily broad, encompassing both organic disease and psychiatric illness. Often the cause is multifactorial. The challenge of the patient presenting to the emergency department (ED) with a complaint of weakness is to develop an adequate database to allow differentiation of the acute organic entities from chronic disease and functional states. Recognition of the potentially life-threatening diseases is critical, whereas the more stable problems may be referred to the appropriate primary care provider. Diagnosing the cause of weakness may be quite difficult, especially early in the disease's presentation. The emergency physician must often make key diagnostic and management decisions with a limited database. This article deals primarily with the patient presenting to the ED with generalized or symmetric weakness that is unrelated to cerebrovascular disease or to central nervous system (CNS) disorders including trauma. It will present a systematic approach to the process of compiling the necessary database for decision-making while simultaneously initiating treatment during key decision points in the evaluative process.