Acute graft vs. host disease (aGVHD) is a major limitation of hematopoietic stem cell transplantation (HSCT), and it causes significant morbidity and mortality for this patient population. This immune-mediated injury occurs unpredictably and is caused by donor-derived T cells reacting to recipient alloantigens. Although donor Th1 cells play a critical role in aGVHD generation, numerous arms of both the innate and the adaptive immune systems along with determinants of lymphocyte trafficking are likely involved in the multifaceted cascade of immunological events that culminates in clinical aGVHD. T regulatory and Th17 cells are T cell subsets distinct from Th1 cells that are likely involved with aGVHD. Regulatory T cells (Tregs) have been implicated in the prevention of aGVHD in both mouse and man, while Th17 cells may modulate early inflammatory responses associated with aGVHD, especially those involving the skin and the lungs. Interestingly, these two lymphocyte subsets appear to be reciprocally regulated in part through retinoic acid, through cytokines such as IL-6, and via interactions with dendritic cells. Another area under tight regulation appears to be the homing of lymphocytes to lymph nodes, skin, and gut. Adhesion molecules including chemokine receptors, selectins, and integrins may identify specific T cell subsets with unique migratory functional properties during HSCT. Controlling the migration patterns of Th17 cells and Tregs represents a potential therapeutic target. A major goal of HSCT research will be to develop approaches to pharmacologically manipulate T cell subsets in vivo or to select, expand, and infuse T cell subsets that will maximize the targeted graft vs. tumor effect while minimizing the potentially fatal side effects of aGVHD. A better understanding of Tregs and their tissue specificity should lead to improvement in the success of HSCT.