Graft-versus-host disease (GvHD), a major complication following allogeneic hematopoietic stem cell transplantation, is mediated by donor-derived T cells. On activation with alloantigens expressed on host antigen-presenting cells, naive CD4(+) T cells differentiate into T-helper cell subsets of effector T cells expressing distinct sets of transcriptional factors and cytokines. Classically, acute GvHD was suggested to be predominantly related to Th1 responses. However, we now face a completely different and complex scenario involving possible roles of newly identified Th17 cells as well as Tregs in GvHD. Accumulating data from experimental and clinical studies suggest that the fine balance between Th1, Th2, Th17 and Tregs after transplantation may be an important determinant of the severity, manifestation and tissue distribution of GvHD. Understanding the dynamic process of reciprocal differentiation of regulatory and T-helper cell subsets as well as their interactions will be important in establishing novel strategies for preventing and treating GvHD.