Death receptor mediated apoptosis plays an important role in a number of thyroid disorders. The present study demonstrated for the first time the in vivo presence of TRAIL and its receptors in the normal thyroid gland and in Hashimoto’s thyroiditis. The TRAIL-mediated apoptosis of thyroid epithelial cells is regulated by inflammatory cytokines. IL-1β alone and in combination with TNFα induces sensitivity to TRAIL, while the further addition of IFNγ makes these cells resistant to apoptosis mediated by TRAIL. This pattern of TRAIL sensitivity correlates with levels of cell surface expression of TRAIL receptors. IL-1β/TNFα enhancement of DR5 surface expression provides a mechanism for TRAIL sensitivity. We have further documented that the signal is mediated through DR5 by the use of DR5 specific agonist antibody. Confirming the essential role of proinflammatory cytokines in the regulation of apoptosis in vivo, the combination of IFNγ and TNFα enhanced thyrocyte apoptosis through the Fas pathway and transformed nondestructive to destructive thyroiditis in a murine model of experimental autoimmune thyroiditis. The majority of goiter-derived thyroid cells cannot be sensitized to TRAIL and/or Fas-induced apoptosis in vitro by inflammatory cytokines, which represents a new aspect of aberrant growth regulation in goiter nodules. The increased proteasome activity associated with this resistance suggests that the proteasome may be an important regulator of apoptosis in nodular goiter. Finally, the hu-PBL-SCID mouse was established for the in vivo investigation of human thyroid cancer. This model is appropriate to examine the biological characteristics of thyroid cancers but warrants improvement to analyze the interaction between the immune system and tumor cells.