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Tall fescue toxicosis continues to be a major syndrome in temperate climates of the world in terms of economic loss to animal producers. Studies with forage-fed animals over the past three decades have provided insight concerning the pathophysiological effects of the alkaloids present in tall fescue [Lolium arundinaceum (Schreb.) Darbysh.] infected with the fungal endophyte Neotyphodium coenophialum (Morgan-Jones and Gams) Glenn, Bacon, and Hanlin. To provide the reader a general understanding of the overall problem, we present a detailed discussion of the clinical signs of fescue toxicosis, the proposed toxicants, and projected solutions to this costly disease condition of ungulates. We also explore the physiological mechanisms proposed to be involved in the expression of the syndrome. Finally, we offer our suggestions for future research efforts in this arena and the potential impact of these approaches.