Since 25 years, my laboratory is focused on understanding the molecular biology of cytokines. Using structure-function analysis approaches, we have in the past defined the binding sites of Interleukin-6 and its two receptor subunits, Interleukin-6-receptor and gp130. This has enabled us to build the first molecular model of the Interleukin-6 receptor complex and was the starting point for the construction of various designer cytokines, which have considerably higher specific biologic activity than the natural cytokines. A second aspect of our work has started with the discovery of a naturally occurring proteolytic cleavage of the Interleukin-6 receptor, which leads to the generation of a soluble Interleukin-6 receptor. We have discovered that the complex of soluble Interleukin-6-receptor and Interleukin-6 stimulates cells, which express the signal transducing receptor subunit gp130 but not the ligand binding subunit Interleukin-6 receptor. In the absence of the sIL-6R such cells do not respond to IL-6. We have called this process 'transsignaling'. We have shown in the past 10 years that 'trans-signaling' is important for the regulation of cellular differentiation and of apoptosis and has a prominent role in inflammation, neuronal survival, hematopoiesis, and tumor defense. We are currently developing the concept that the triggering of 'transsignaling' is an emergency reaction of the human immune system and that disruption of 'trans-signaling' can be used therapeutically for the treatment of chronic inflammatory diseases and cancer. Indeed, one cytokine antagonist, which – in animal models – has proven effective in blocking chronic inflammatory diseases such as Crohn’s diseases, Rheumatoid Arthritis and inflammatory colon cancer, is now tested in Phase I clinic trials since June 2013.