There is much current clinical, pathological and scientific interest in infective disorders of the central nervous system, particularly those associated with the human immunodeficiency virus (AIDS) and the transmissible human spongiform encephalopathies (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia). To investigate these disorders it is necessary to develop and follow procedures for performing autopsies on known or suspected cases which allow both diagnostic and research investigations to be carried out, while at the same time presenting minimal risk to pathologists, mortuary and laboratory technical staff. This article reviews the objectives for performing 'high-risk' autopsies, and summarizes current guidelines for autopsy procedures and laboratory tissue handling in light of extensive experience in the Neuropathology Laboratory, University of Edinburgh. Neuropathology has a leading role to play in diagnosis and research in this important field; the need for 'high-risk' autopsies is likely to increase into the next century.