When faced with a daunting scientific quest, it is perhaps best to start by laying out a simple road map of the journey that lies ahead. A useful road map in the pursuit of transplantation tolerance is that of the primary immune response (Figure 2). Upon exposure to a foreign antigen, whether a potentially lethal virus or a life-saving organ transplant, antigen-specific T cells proliferate extensively (the expansion phase) and acquire effector functions that allow them, with the help of B lymphocytes and other mononuclear cells, to eliminate the foreign intruder. T cell expansion, however, does not continue indefinitely but comes to a quick halt as autoregulatory mechanisms ensure that most effector T cells generated during the immune response are eliminated by apoptosis (the death phase). The few lucky T cells that survive the death phase become long-lived memory T cells that confer life-long protection against the foreign antigen (the memory phase). Therefore, the central question in the quest for transplantation tolerance is how to coerce an immune response determined to generate T cell memory into a state of blissful unresponsiveness.