Hematopoietic stem-cell transplantation is potentially curative treatment for malignant and non-malignant diseases. The development and severity of graft-versus-host disease (GVHD) is strongly related with post-transplant outcomes. GVHD may at the same time improve survival by decreasing the risk of disease relapse and increase non-relapse mortality by causing organ failure and predisposing the recipient to life-threatening infections. Currently available classifications attempt to separate GVHD into subgroups according to their risk of post-transplant death. The heterogeneity of both acute and chronic GVHD is a major barrier for a clear recognition of these subgroups. Multiple organ involvement and severity of organ dysfunction are the hallmarks of GVHD classifications. The development of GVHD is also predicted by a number of factors related to GVHD prophylaxis, donor type, degree of HLA matching, graft source, and conditioning regimen intensity. These factors not only affect the development of GVHD, they may independently be associated with survival. Modulation of GVHD risk factors can decrease the risk or severity of GVHD but does not universally result in an improvement in survival. Additional risk factors present after the onset of GVHD - including thrombocytopenia, hyperbilirubinemia, previous acute GVHD, extensive skin involvement, among others - further increase the risk for GVHD-related mortality. Recognition of such key factors assists in determining a population with high-risk GVHD that would benefit from up-front experimental therapies in the context of clinical trials.