Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GVHD due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In addition, the beneficial antitumor activities were largely preserved in NFAT-deficient effector T cells. Here, NFATC1 is linked to graft versus host disease.