Jejunal hemorrhage syndrome (JHS) is an acute, highly fatal enterotoxemic disorder in dairy cattle that has been reported during the last few decades. No specific cause of this syndrome has been identified; however, several studies have revealed a strong association between JHS and infection with Clostridium perfringens type A. A common mold, Aspergillus fumigatus, has also been implicated as a potential causative agent in this disease syndrome. Clinical signs of JHS (including sudden decreases in feed intake and milk production, rapid loss of condition, a right-sided ping audible during simultaneous auscultation and percussion of the abdomen, abdominal distension, and melena or bloody feces) usually develop early during lactation when cattle receive rations that are high in energy and low in fiber. Appropriate preventive strategies have not yet been determined, and intensive medical management with or without surgical intervention is rarely successful. The use of commercially available vaccines that are directed against C perfringens types C and D is of questionable efficacy and not likely to be helpful as a preventative measure. This article highlights the potential etiologic and risk factors, describes common clinical signs, outlines relevant diagnostic testing, and summarizes treatment options and their outcomes.