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.) DarbyshJ 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. T all fescue is an economically important cool-season perennial forage grass covering about 15 million ha in the United States alone (Buckner et al., 1979) and many more in continents outside North America (see Chapter 3, Hannaway et alv 2009, this publication). The vast majority of the tall fescue in the United States is grown within the transition zone of the eastern and central part of the country. With the development of novel nontoxic endophytes, tall fescue is again becoming increasingly popular for pastures in New Zealand and Australia. The wide distribution of tall fescue has been attributed to its symbiotic relationship (see Chapter 14, Christensen and Voisey, 2009, this publication) with the endophytic fungus Neotyphodium coenophialum (Glenn et al., 1996). Although beneficial to