To provide protection against all foreign pathogens one can possibly encounter during their lifetime, the T cell repertoire has to be as diverse as possible. At the same time, it is desirable that the T cell repertoire remains unresponsive towards healthy tissues. To realize this self/nonself discriminatory property, T cells undergo tightly controlled selection processes during maturation in the thymus. The key parameter determining the outcome of these selection processes is the avidity of the T cells for self-MHC/self-peptide complexes expressed in the thymus; low avidity interactions result in positive selection, whereas high avidity interactions lead to negative selection. Despite the selection processes, self-tolerance is far from absolute. In many cases, this is due to the presence of self-antigen in the thymus at a level that is too low to induce thymic deletion. In addition, T cells with a low avidity for ubiquitously expressed self-antigens can escape clonal deletion and enter the periphery. A thorough understanding of the self-specific T cell repertoire is important because many potential targets for cancer immunotherapy are self-proteins. In this review, the authors discuss the impact of self-antigen expression on the CD8+ T cell repertoire. An overview of the fate and functional capacities of self-specific T cells with specificity for tissue-restricted self-antigens and for ubiquitously expressed self-antigens is provided. Furthermore, the authors discuss the influence of negative selection on the antitumor reactivity of the mature T cell repertoire.