Recent investigations have solidified the importance of negative selection in controlling autoimmunity. Loss of autoimmune regulator (AIRE), required for thymic stromal-cell differentiation and thymic expression of peripheral antigens, results in multi-organ autoimmunity. Mice with AIRE/Foxp3 double mutations suffer from exacerbated autoimmunity when compared with mice with only one mutation, supporting the important contributions of both central and peripheral tolerance. In thymocytes, Cbl is a negative regulator of thymocyte apoptosis while MINK, a MEKK kinase, is required for negative selection. This is consistent with the requirement of JNK, p38 and possibly ERK5 MAP kinases in thymocyte apoptosis. ERK5 induces the Nur77 orphan steroid receptor family members. In cell lines, Nur77 interaction with Bcl-2 turns Bcl-2 into a pro-apoptotic molecule. This and other possibilities will be discussed to explain the unresolved finding that negative selection is defective in Bim(-/-) but is not efficiently blocked in Bcl-2 transgenic mice.