Since its discovery in 1986, originally as B cell stimulating factor 2, the knowledge on IL-6 for immune homeostasis and its pathophysiological implications has rapidly increased. It is now clear that IL-6, alone or in combination with other cytokines, is an architect for shaping and generating immune responses which exerts profound activities on the induction of acute-phase reactions, the differentiation of B lymphocytes, the modulation of T cell apoptosis, the activation of T helper cells and the balance between regulatory T cells and Th17 cells. In parallel to the identification of these physiologic functions, IL-6 has emerged as a critical mediator for perpetuating chronic inflammation and autoimmunity and is increasingly recognized as a key cytokine for linking chronic inflammation to cancer development. In this review, we begin by briefly summarizing the molecular events of IL-6 regulation and signaling and then describe the role of IL-6 in orchestrating innate and adaptive immune responses and its immunopathological relevance for chronic inflammatory diseases. We further outline how IL-6 links chronic inflammation and cancer development and finally provide an outlook on novel therapeutic strategies targeting IL-6 signaling for the treatment of chronic inflammatory diseases and cancer.