Many insights have been gained into cytokine-regulated control of inflammatory processes and host defence in recent years. Evidence has also gradually accumulated that cytokine cascades play a central role in events regulating cell death and differentiation. Further developments include an understanding that the biological effects of the tumor necrosis factor-alpha (TNF-α or TNFSF) cytokine may be regulated by soluble TNF receptor binding and that modulation of receptor levels may permit physiological inhibition of TNF action. There has been a gradual realisation of the value of TNF/TNFR ratios as predictors of disease outcome, and the discovery of functional regulatory polymorphisms of the TNF gene and mutations of TNFRSF1A (TNFR1 receptor) have led to conceptual breakthroughs in our understanding of the genetic control of inflammation. However the exact mechanisms by which TNFRSF1A mutations give rise to disease susceptibility are not yet well understood. Over the past 10 years these concepts have been used as the basis for successful anti-TNF therapy of autoimmune diseases like rheumatoid arthritis (RA) and Crohn’s disease.