Simple SummaryYellow lamb disease is a poorly researched and understood condition that seems to affect young sheep. The disease is characterized by hemolysis and is thought to be caused by alpha toxin-producing Clostridium perfringens type A, although a definitive association with this microorganism has not been confirmed. This is due, in part, to the ubiquitous nature of C. perfringens type A, which is naturally present in the intestine of healthy sheep, a fact that complicates the diagnosis. In this review, we summarize the available information on the etiology, clinical signs, lesions, diagnosis, prevention and prophylaxis of yellow lamb disease.Yellow lamb disease is an infrequent disease in sheep for which there is scant literature, and that has been reported in the US, Australia, New Zealand, South Africa and Europe, although anecdotal evidence indicates that it may have also been diagnosed in South America. The disease is produced by some strains of Clostridium perfringens type A that produce unusually high levels of alpha- toxin. Because C. perfringens type A is ubiquitous and is found in the intestine of most clinically healthy sheep, diagnosis of yellow lamb disease is challenging and requires quantitating the amount of this microorganism present in feces and/or intestinal content. Clinically, yellow lamb disease is characterized by depression, anemia, icterus and hemoglobinuria. Occasionally, sudden death may occur. Gross findings include generalized icterus, red urine in the bladder, enlarged, pale, and friable spleen, enlarged liver with an acinar pattern, and dark, swollen kidneys. Microscopically, yellow lamb disease is characterized by centrilobular necrosis of the liver, hemoglobinuria-associated acute tubular injury, splenic congestion, pulmonary congestion and edema. Although there are no vaccines specifically designed to prevent yellow lamb disease, several vaccines against the different types of C. perfringens may afford at least some level of protection against yellow lamb disease.