Clostridial dermatitis (CD) is a multifactorial disease of rapidly-growing turkeys. Clostridium septicum (Cs) has been identified as the primary cause, although C. perfringens (Cp) has also been implicated. Pathogenesis is not fully understood; however, it is hypothesized that Clostridia translocate from the gastrointestinal tract and spread hematogenously to capillary beds of skeletal muscles. Intense genetic selection has produced a rapidly growing bird that is heavier and less active. This may predispose birds to development of CD due to positional restriction of blood flow to the caudal breast and medial thigh. Subsequent reduction in oxygen tension within these tissues produces conditions conducive to germination, proliferation, and toxin production by previously trapped, non-replicative Clostridia. Studies were undertaken to investigate the epidemiology and pathophysiology of CD. Retrospective epidemiologic investigations evaluated incidence, risk factors, and economic impact of CD. Cs and Cp qPCR were performed on blood and tissue samples to demonstrate hematogenous spread in asymptomatic birds. Studies assessed the effect of prolonged recumbency by measuring oxygen saturation and surface temperature in dependent tissues. Tissues from CD cases were evaluated for Cs and Cp alpha toxin mRNA (CsA and CpA). Analyses were conducted to determine associations between these toxins and severity of histopathologic lesions. Whole genome sequencing was performed on the Cs type strain to identify other toxin genes. Flock type, breed, weight at time of processing, and stocking density affected disease incidence. Detection of Clostridium spp. in intestine, liver, and muscle from asymptomatic turkeys without cutaneous trauma implies hematogenous spread from an endogenous source. Focal polyphasic myonecrosis in dependent muscles of asymptomatic turkeys suggests an underlying predisposition to development of CD. Recumbency appeared to be associated with decreased perfusion to these tissues. Cs DNA was present in asymptomatic birds without corresponding CsA mRNA expression suggesting that organisms were present in a quiescent form. CsA was associated with CD while CpA did not appear to be involved in pathogenesis. Genome sequencing identified several coding regions which may correspond to other potentially active Cs toxins. These results support the proposed mechanism of pathogenesis and provide targets for further investigation of disease pathophysiology and vaccine development. / Ph. D.