Excluding JAKs, increasing data have demonstrated that targeting signaling pathways, such as the PKCα and PKCθ (66), MEK (68), NFAT (65), and IRE-1a/XBP-1 pathway (67), ikaros (107), toll-like receptor/myeloid differentiation factor 88 (108), DR3 signaling (94), and activated protein C signals (95), might provide strategies for alleviating GVHD, while enhancing or without compromising the GVL effects. This evidence concerns the gene TNFRSF25 and graft versus host disease.