High-dose chemotherapy followed by allogenic stem cell transplantation has been extensively used for the treatment of patients with hematological malignancies. Unfortunately, this life saving procedure is limited to a subset of patients who are in good medical condition due to the increased risk of regimen-related toxicity and graft-versus-host disease that occur with increasing age and poor performance status. On the other hand, it became apparent that the curative potential of transplantation was not solely due to the conditioning regimen but also to the graft-versus-leukemia effect mediated by alloreactive donor T cells. These observations led to the development of new transplant strategies using less intensive preparative regimens that would allow donor cell engraftment without the toxicity of myeloablative conditioning as a method of exploiting a graft-versus-malignancy effect in patients ineligible for conventional marrow grafts. Although follow-up is relatively short, preliminary results are encouraging and demonstrate the feasibility of non-myeloablative transplants in patients with heterogeneous diseases and disease status who Current challenges include defining the optimal regimen to promote full donor engraftment and the malignancies susceptible to this approach. The present review summarizes the most recent results obtained in this attractive field.