Allogeneic HCT after myeloablative conditioning is an effective therapy for patients with hematologic malignancies. In an attempt to extend this therapy to older patients or those with comorbidities, reduced intensity or truly nonmyeloablative regimens have been developed over the past decade. The principle underlying reduced intensity regimens is to provide some tumor kill with lessened regimen-related morbidity and mortality and then rely on graft-versus-tumor (GVT) effects to eradicate remaining malignant cells, whereas nonmyeloablative regimens rely primarily on GVT effects. In this article, 3 representative approaches are described, demonstrating the clinical application for hematopoietic and nonhematopoietic malignancies. Current challenges include controlling GVHD while allowing GVT to occur. In the future, clinical trials using reduced intensity and nonmyeloablative conditioning will be compared with myeloablative conditioning in selected malignancies to extend the application to standard-risk patients.