Transplantation of allogeneic hematopoietic stem and progenitor cells (allo-HCT) allows for cure of life-limiting malignant and non-malignant hematologic diseases. Crossing the human leukocyte antigen (HLA) barrier, however, comes at the cost of graft-versus-host disease (GVHD), a life-threatening syndrome mediated in part by the same donor T-lymphocytes that eliminate malignant cells. Acute GVHD occurs in the skin, gut, and/or liver in 25–55% of patients with a mortality rate of 15–40%, while chronic GVHD develops in 30–65% of patients who survive at least 3 months following allo-HCT and is highly debilitating in its extensive form, with a 30–50% 5 year mortality rate stemming in part from immune dysregulation and opportunistic infections. Knowledge gaps remain in understanding the pathogenesis and in developing novel and effective treatments for the acute and chronic GVHD, which have distinct biology and yet are both treated with front line systemic corticosteroids. Novel and informative mouse models remain the primary means by which these diseases are studied and drugs initially developed prior to testing in humans. In this chapter, we describe allo-HCT mouse models and protocols using these mouse models by which to study acute and chronic GVHD with the goal of improving prevention and therapy.