Much effort is currently directed towards generating and evaluating agents that target the individual components of the alloimmune response, with a view to promoting allograft survival accompanied by minimum side effects. Recently, there has been considerable interest in inhibiting individual cytokine/receptor interactions since they are key elements in pathways for differentiation of immune effector cells. This article examines the utility of targeting interactions of interleukin (IL)-15 with its receptor as a strategy for disabling the T-cell activation events following recognition of foreign major and minor histocompatibility antigens. Experimental evidence suggests that interrupting IL-15/IL-15R interaction may be of therapeutic value in preventing allograft rejection.