The thymus is a complex organ that performs its critical function through the action of several key groups of cells that are located in spatially distinct areas of the thymus: cortical thymic epithelial cells, medullary thymic epithelial cells, and medullary dendritic cells. Negative selection occurs in the thymus when dendritic cells (DCs) presenting self-antigens interact with CD4+CD8+ double-positive thymocytes that express a self-reactive T-cell receptor. Expression of major histocompatibility and costimulatory molecules on the DCs are considered the major factors determining the fate of thymocytes. Accumulating evidence suggests that additional factors including cell-to-cell interactions between thymocytes and permanent thymic resident cells as well as the presence of local cytokines and soluble mediators that act on thymocytes through the JAK-STAT pathway, or through Nur77 or ROR?t signaling pathways, can also play an important role to refine the selection process. This chapter will describe key cytokines and nuclear hormone receptors that act 42together at different stages of thymocyte development to mediate thymocyte survival and apoptosis. The connection of IL-23 in influencing T-cell diversity and regulation in the periphery through a central mechanism is also described.