Acute graft-versus-host disease (GVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). The classical target organs of acute GVHD include the intestines, liver, and skin. The damage of these organs is relatively easy to detect for the clinician as diarrhea, increased bilirubin, and rash. However, there is increasing evidence that other organs, where the acute damage is less apparent or more difficult to distinguish from drug toxicity, such as the central nervous system, lungs, ovaries and testis, thymus, bone marrow, and kidney, can be target organs of acute GVHD. Here, we review current evidence for nonclassical manifestations of acute GVHD in rodent models and in patients and discuss them in the context of novel emerging therapies for GVHD. A better understanding of the involvement of nonclassical GVHD target organs may help to improve patient outcomes after allo-HCT.