Establishment of self‐tolerance prevents autoaggression against organ‐specific self‐antigens. This beneficial effect, however, may In turn be responsible for tumor immune evasion. Thus, dissecting the mechanisms leading to the breakdown of self‐tolerance in autoimmune diseases might provide insights for successful antitumor immune therapies. In a variety of animal models, organ‐ or tumor‐specific immunity has been described, focusing on antigen‐specific T‐cell activation. Here, we discuss two trans ‐genic mouse models which demonstrate that both autoaggression and tumor rejection require more than activated, self‐reactive T cells. TCR transgenic mice, which are tolerant to a liver‐specific MHC class I antigen, K^b, can be activated to reject Kb^b‐positive grafts, but fail to attack K^b‐expressing liver. However, autoaggression occurs when activated T cells are combined with “conditioning” of the target organ by irradiation or infection with a liver‐specific pathogen. Similarly, in a mouse model of islet cell carcinoma, neither co‐stimulatory tumor cells nor highly activated antitumor lymphocytes provoke an effective immune response against the tumor. Instead, a combination of activated lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated antigen‐specific lymphocytes are a prerequisite for autoaggression, effector cell extravasation and appropriate interaction with the target organ/tumor are equally important. Thus, we propose that the organ/tumor microenvironment is a critical parameter in determining the effectiveness of an anti‐self immune response.