Graft-versus-host disease (GVHD) is a serious and potentially fatal complication that occurs after allogeneic hematopoietic cell transplantation. It is characterized by the immune response of the graft (from the donor) against the tissue of host (recipient), resulting in damage to target organs such as the skin, liver, and intestines. Understanding the underlying mechanisms of GVHD is crucial for improving treatment and prevention strategies for this debilitating condition. Animal experimental models play a key role in this process, allowing for the investigation of immune mechanisms and the evaluation of new therapies. These models provide valuable insights into the pathophysiology of GVHD and help develop more effective therapeutic approaches to improve clinical outcomes in transplant patients. In this chapter, we provide a brief overview of allogeneic and semi-allogeneic models of GVHD in mice. Then, we will address the step-by-step process for inducing experimental GVHD in mice using an allogeneic model in mice with total body irradiation myeloablation.