This article discusses the etiology, mechanism of action, clinical signs, and diagnostic tests used to identify toxic agents that affect the nervous system of ruminants. The article is not intended to be an exhaustive review of each agent, but a reference for establishing a differential diagnosis when toxic agents are suspected as the cause of central nervous system disease in ruminants. The initial focus of the article is on agents that cause brain lesions consistent with polioencephalomalacia. Other neurotoxic disease agents include bovine bonkers, urea, organophosphate, organochlorine, cyanobacteria, zinc, aluminum, phosphide, metaldehyde, strychnine, botulism, tetanus, clostridium perfringens, and poisonous plants.