Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disorder of the CNS of unknown etiology that progressively affects the upper and lower motor neurons at the spinal or bulbar level. It usually affects patients > 50 years old. The presenting symptoms typically include weakness and clumsiness of the hands. Muscle cramps and fasciculations commonly occur early in the course of the disease, with progressive involvement of the muscles of the lower extremities, trunk, and neck. Weakness of the diaphragm subsequently ensues. This pattern of muscle weakness results in a clinical presentation characterized by limb muscle weakness followed by respiratory symptoms late in the clinical course of the disease. The presence of upper and lower motor neuron involvement with progressive weakness strongly suggests ALS. Such patients should undergo nerve conduction studies with repetitive stimulation and electromyography to confirm lower motor neuron degeneration and exclude disorders of peripheral nerves and muscles in addition to disorders of the neuromuscular junction, such as myasthenia gravis. Routine clinical laboratory tests are necessary to exclude other neurologic disorders caused by metabolic and endocrine conditions, plasma cell dyscrasias, and heavy metal poisoning. These tests should include blood glucose, thyroid function tests, parathyroid hormone level, calcium and phosphate, vitamin B12 and folate levels, serum protein electrophoresis, and a urine collection for heavy metals.