CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7(-/-)) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7(-/-) T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7(-/-) T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7(-/-) T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7(-/-) T cells were capable of generating robust graft-versus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7(-/-) regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.