T lymphocytes play a critical role in adaptive immunity to pathogens. Their ability to function properly in this role, while not causing an immune reaction to host tissues, reflects cellular properties that are established as they develop in the thymus. For this reason, immunologists have long studied the thymus, and many mouse models that facilitate that these analyses exist. This chapter discusses the utility and limitations of transgenic and gene-deficient mouse strains to model thymic processes, specifically negative selection. Clonal deletion is a fundamental process necessary to maintain tolerance to self-antigens. As demonstrated by the occurrence of multi organ autoimmunity in the face of impaired negative selection to tissue-specific antigens in autoimmune regulator-deficient mice or humans, understanding the factors controlling deletion is of great importance. When one is using mice as a model system to study negative selection, it is critical to choose an appropriate model as data concerning the role of a molecule in negative selection from one model are not always the same as those in another model. Given that the medulla is replete with potent antigen-presenting cells, late deletion models appear to be the most physiological. Further work examining the molecular pathways leading to deletion, specifically those involved in delivering the apoptotic signal, is greatly needed at this juncture.