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Graft-versus-host disease (GVHD) is an untoward complication of bone marrow transplantation. It is characterized by an immune-mediated attack by donor immune cells against various host cells and tissues, a process which may be associated with significant morbidity in affected patients. Oral lesions are a common sequelae and can serve as a highly predictive index to the presence of systemic GVHD. The oral lesions of GVHD are clinically and histologically lichenoid in nature and can be a challenge in terms of management. Ulcerated and painful mucosal lesions may represent a significant impediment to normal eating habits and nutritional intake, necessitating appropriate diagnosis and treatment. Importantly, recent evidence has indicated that programmed cell death, or apoptosis, is the major constituent in the pathogenesis of GVHD. Apoptosis not only plays a major role in normal growth and ontogeny, but has been shown to contribute to a wide spectrum of both inflammatory and neoplastic disorders. Since knowledge of apoptotic molecular pathways is requisite for understanding GVHD, the purpose of this paper is to provide a fundamental overview of the predominant apoptotic mechanisms implicated in the pathogenesis of GVHD and to relate these findings to the oral complications of the disease. Finally, we will discuss management strategies for diagnosing and treating the oral lesions of GVHD. By explicating the molecular events in the apoptotic pathway, unique therapeutic and pharmacologic strategies for regulating apoptosis may be developed in the future, reducing the morbidity associated with conditions like GVHD.