Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments. Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care, are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosis—including dysphagia, dysarthria, respiratory distress, pain, and psychological disorders—and care in the terminal phase. The need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview of some current major issues and future prospects, ranging from the search for disease markers to challenging developments such as stem-cell and gene therapy.