Allogeneic stem cell transplantation is an effective and potentially curative therapy for hematologic malignancies. However, the procedure may be associated with significant morbidity and mortality resulting from toxicity of the conditioning regimen, limiting it to younger patients in good medical conditioning. Over the past decade, nonmyeloablative and reduced-intensity conditioning regimens have been designed to reduce toxicity and allow stem cell transplantation in elderly and medically infirm patients. These are relatively nontoxic and tolerable regimens designed not to maximally eradicate the malignancy, but rather to provide sufficient immune suppression to achieve engraftment and to allow induction of graft-versus-leukemia effect as the primary treatment. After transplantation, immune interventions are often required to hasten this graft-versus-leukemia effect. In this review, we discuss emerging data defining the relative toxicities and outcomes after nonmyeloablative transplantation in certain settings and our approach to patient selection and post-transplant immune interventions trying to improve overall outcome.