Non-myeloablative preparative regimens have reduced regimen-related toxicities after allogeneic hematopoietic cell transplantation (HCT), which allows for the treatment of patients not eligible for myeloablative HCT. The reduced non-relapse mortality associated with non-myeloablative HCT is in part explained by the decreased incidence and severity of acute graft-vs-host disease (GVHD). Compared with conventional HCT, the onset of acute GVHD is delayed, and some patients may present with signs and symptoms characteristic of acute GVHD after day 100, in the absence of hallmarks of chronic GVHD. In contrast to the overall negative impact of acute GVHD on outcome, the net effects of chronic GVHD after non-myeloablative HCT appear to be beneficial, translating into improved progression-free survival among patients with different hematological malignancies. One obvious explanation for this beneficial effect is the strong association between chronic GVHD and protection against recurrent malignancy (graft-vs-tumor effect). Future strategies are aimed at reducing the risk of acute GVHD, in particular "early-onset" GVHD (before day 50), which is associated with increased non-relapse mortality and decreased overall survival, and at decreasing the corticosteroid dependence among patients who require immunosuppressive treatment for clinically established GVHD.