Tumor necrosis factor alpha is increasingly being recognized as an important macrophage-derived cytokine that possesses pleomorphic effects in both physiologic and immunologic systems. Current evidence has demonstrated that tumor necrosis factor may stimulate a plethora of cellular responses in vitro and induce multiple physiologic derangements when given in vivo. While the biologic activity of tumor necrosis factor elaborated by macrophages and macrophage cell lines in response to bacterial and protozoal cell products have been well documented, the endogenous factors that regulate the production of this monokine are not as clearly delineated. This chapter focuses on the cellular and molecular mechanisms that endogenously regulate the production of tumor necrosis factor.