The vast and growing array of cytokines is the subject of intense research for their potential to ameliorate a range of diseases that extends from autoimmune disorders to cancer and beyond. Among the cytokines, tumor necrosis factor-alpha (TNF-alpha) has proven to be a key ligand in triggering many intracellular processes, both physiological and pathological. Understanding its role in rheumatoid arthritis and Crohn's disease has produced effective new therapeutic agents, and there is reason to expect greater success as research proceeds. New synthetic macromolecules are effectively interfering with TNF and other ligands at and before the cellular membrane interface. This article reviews current knowledge of the molecular mechanics of TNF and the therapeutic inhibition of TNF action. Unraveling these processes has led to many insights into cytokine physiology and pathology.