Salmonid species and sub-species exhibit a range of susceptibility to Myxobolus cerebralis infection. Little is known about lesion severity and location, or time required for M. cerebralis myxospores to develop in Yellowstone cutthroat trout Oncorhynchus clarki bouvieri. In 2002 we performed three 10 d exposures of Yellowstone cutthroat trout fry in Pelican Creek, an M. cerebralis-positive tributary to Yellowstone Lake. At 90 and 150 d post-exposure we examined the fish for clinical signs, for infection prevalence, and by histology to determine M. cerebralis infection location and severity of lesions. The most prevalent clinical signs in Yellowstone cutthroat were whirling behavior and skeletal deformities, especially at 90 d post-exposure. Prevalence of infection and severity of cartilage lesions were not statistically different between fish held for 90 or 150 d post-exposure. Histopathology was most severe in cartilage of the cranium and the lower jaw, whereas cartilage of the nares and gill arches was seldom damaged. This study suggests that Yellowstone cutthroat trout are highly vulnerable to M. cerebralis and that current population declines in the Yellowstone Lake basin may, in part, result from whirling disease. Our results answer important questions in fish health and will aid in the development of diagnostic tools and management efforts against this pathogen in native cutthroat trout and other vulnerable salmonids.