CD8 T cells specific for self-antigens are present in the peripheral lymphoid system and can contribute to autoimmunity or transplant rejection. Whether recognition of Ag leads to full activation, or to induction of tolerance, depends upon availability of cytokine at critical stages of the response. Signals provided by IL-12 and/or IFN-alpha/beta are required for activation of naïve CD8 T cells, and IL-2 is needed to sustain and further expand the effector cells if Ag persists. These critical signaling requirements provide new insights into the factors that regulate the CD8 T cell contributions to development of autoimmunity or rejection of transplants.