Development of reduced-intensity conditioning regimens (RIC) has enabled older or medically infirm patients with hematologic malignancies to be treated with allogeneic hematopoietic cell transplantation (HCT). This broader transplant eligibility has tripled the number of RIC-HCT procedures performed each year, with over 3000 in 2012. Currently about 50% of RIC-HCTs use unrelated donors, since many patients are older and do not have matched sibling donors. Naturally, this makes graft-versus-host disease (GVHD) prevention of particular importance. The ideal GVHD prophylaxis must balance tumor control/GVL with toxicity/GVHD. In this review, we discuss challenges in developing effective GVHD prophylaxis for RIC-HCT, various GVHD prophylactic regimens that are sometimes specific to the conditioning regimen, and the evidence to support their use.