Ergothioneine (ET) is a diet-derived compound that is avidly absorbed and retained by the human body using a specialised transporter, OCTN1. A substantial and growing body of evidence implicates ET in maintaining human health and protecting against age-related diseases, especially neurodegenerative diseases, and multiple studies indicate that low blood ET levels increase the risk of developing age-related diseases. Despite the growing interest in ET, much fundamental work remains to be done on its metabolism, intracellular and intercellular transport (especially in the brain), precise mechanisms of cytoprotection, interactions with the microbiome, mycobiome and human pathogens, and identifying the factors that control body ET levels. This narrative review explores these issues and suggests what research needs to be done to improve our understanding of ET biology.