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The establishment and maintenance of T cell tolerance to self- and non-pathogenic foreign antigens is critical for immune homeostasis. Thymic deletion of self-reactive T cells is an important component of tolerance, but it is incomplete, and does not establish tolerance to most foreign antigens. Thus, mechanisms of peripheral tolerance are also required. This is especially true for CD8+ T cells, which are able to encounter their cognate antigens presented by nearly any cell type. Upon differentiating into cytotoxic T lymphocytes (CTL), CD8+ T cells do not require costimulation for their cytotoxic function, reinforcing the importance of tolerance in these cells. In this review, we will discuss the modes of peripheral tolerance in CD8+ T cells, covering both naïve and effector T cells. We will examine the antigen and signaling requirements for tolerance induction and maintenance, and will also touch on similarities and potential differences between CD8+ and CD4+ tolerance mechanisms.