Significance Of the many receptors that were pharmacologically described during the 20th century, almost all were cloned by the end of the 1990s. A key exception is the σ ₂ receptor, a potential therapeutic target for diseases as diverse as schizophrenia, Alzheimer’s disease, and cancer. Despite the development of a rich pharmacopeia, the unknown molecular identity of the receptor has crippled biological investigation. Here, we identify the σ ₂ receptor as TMEM97, a membrane protein implicated in cancer and a binding partner of Niemann–Pick disease protein NPC1. Our results unite two fields of research, bringing the σ ₂ receptor into the modern age of biological inquiry and providing the TMEM97 field with a rich pool of ligands and pharmacological tools.