Allogeneic hematopoietic cell transplantation has developed into a most successful form of immunotherapy for hematologic malignancies in the past 50 years. However, its effectiveness and wider applications have been greatly limited by the development of graft-versus-host disease (GVHD), a potentially lethal side effect associated with this procedure. Since the main effectors for both graft-versus-leukemia (GVL) effect and GVHD are T lymphocytes and these two processes share many similar pathways, it has not been easy to separate GVL from GVHD. Because the clinically used pan immunosuppressive therapy for GVHD prevention also results in decreased GVL effect, the success of allogeneic hematopoietic cell transplantation relies on a small and unpredictable therapeutic window at the present time. This review discusses how we may widen this therapeutic window so that we can reliably prevent GVHD without losing GVL effect.