The pleiotropic cytokine Interleukin-6 (IL-6) fulfills important homeostatic functions, as it is e.g. crucial for differentiation and proliferation of cells of the immune system. Activation of target cells occurs either via the membrane-bound IL-6 receptor (IL-6R, ‘classic signaling’) or soluble forms of the IL-6R (sIL-6R, ‘trans-signaling’). Both signaling entities lead to the formation of a homodimer of the ubiquitously expressed signal-transducing beta-receptor gp130, which induces signaling cascades like the Jak/STAT pathway. We have recently shown that a third mode of signaling for IL-6 exists, in which dendritic cells (DCs) trans-present IL-6 via their own IL-6R to cognately interacting T cells (termed IL-6 ‘cluster signaling’). Trans-presentation of IL-6 leads to activation of the Jak/STAT pathway via gp130 in the T cells and subsequently to the development of pathogenic Th17 cells. IL-6 cluster signaling in DCs is also crucial for pathogenic Th17 cell generation in vivo, and mice with a DC-specific deletion of either IL-6 or the IL-6R are therefore protected in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, the identification of a third way of IL-6 signaling opens up new ways to treat Th17 cell-driven diseases. However, trans-presentation of IL-6 also occurs in other organs, e.g. the liver, and is probably not only limited to T cell differentiation. The different modes of IL-6 signaling have to be taken into consideration when designing therapeutics that are directed against IL-6.