Surface expression of CD4 or CD8 is commonly used to identify T-cell subsets that recognize antigen presented by class II MHC or class I MHC, respectively. This holds true for T cells that respond to allogeneic MHC molecules that are directly recognized as foreign, as well as peptides from allogeneic MHC molecules that are indirectly presented by self MHC molecules. CD4 or CD8 expression was initially believed to define cytokine secreting helper T cells or cytotoxic cells, respectively. However, this association of phenotype and function is not absolute, in that CD4+ cells may possess lytic activity and CD8+ cells secrete cytokines, notably IFNgamma. Recently, additional fundamental differences in the immunobiology of these T-cell subsets have been identified. These include differences in costimulatory requirements, cytokine responsiveness, cytokine production, cell survival, and the maintenance of memory. This review will survey these differences, emphasizing alloreactive T-cell responses as well as relevant observations that have been made in other systems.