Henry McIlwain is usually remembered for his major contributions to the discipline of neurochemistry. He also had a profound influence on electrophysiology by inventing and establishing the brain slice technique. This article describes some of his pioneering studies where he devised ways of preparing, both manually and mechanically (using the McIlwain tissue chopper), viable slices of mammalian cortical tissue and showed how these could be maintained in a brain slice chamber. His work with Choh-Luh Li (Li and McIlwain, 1957) on the first intracellular recording from brain slices and his work with Chosaburo Yamamoto (Yamamoto and McIlwain, 1966) describing the first study of synaptic transmission in brain slices are highlighted. In these studies, McIlwain started the use of brain slices to investigate functional anatomy, to study the effects of hypoxia and hypoglycaemia, to perform quantitative pharmacological analyses and to study synaptic plasticity: investigations which continue today to provide important insights into the functioning of the brain in health and disease.