Interleukin-6 (IL-6) is a cytokine with pro- and anti-inflammatory functions. Interestingly, its divergent biological activities are mediated by different signaling pathways: In IL-6 classic signaling, which is associated with the regenerative and anti-inflammatory properties of the cytokine, IL-6 binds to and signals via the membrane-bound IL-6 receptor (IL-6R) on its target cells. In contrast, the pro-inflammatory properties of IL-6 are mediated via the soluble (s)IL-6R (IL-6 trans-signaling). Recently, a third mode of IL-6 signaling was revealed, which was termed cluster signaling and is required for the generation of pathogenic Th17 cells. In all pathways, intracellular signaling cascades are activated via the formation of a gp130 homodimer. The involvement of IL-6 in the pathogenesis of inflammatory diseases, autoimmune diseases and even cancer has made IL-6 and the IL-6R important therapeutic targets. Consequently, antibodies that block either IL-6 itself or the IL-6R are in clinical use and have been approved for different inflammatory diseases, including rheumatoid arthritis (RA). This review gives an overview about the complex biology of this important cytokine, summarizes the current usage of anti-IL-6 therapeutics in clinical use and highlights the pre-clinical and clinical development of novel therapeutic agents that specifically block only the trans-signaling pathway of IL-6.