Interleukin 6 (IL‐6) performs a prominent role during disease and has been described as both a pro‐ and anti‐inflammatory cytokine. A key feature in the regulation of IL‐6 responses has been the identification of a soluble interleukin 6 receptor (sIL‐6R), which forms a ligand‐receptor complex with IL‐6 that is capable of stimulating a variety of cellular responses including proliferation, differentiation and activation of inflammatory processes. Elevated sIL‐6R levels have been documented in numerous clinical conditions indicating that its production is coordinated as part of a disease response. Thus, sIL‐6R has the potential to regulate both local and systemic IL‐6‐mediated events. This review will outline the central role of sIL‐6R in the coordination of IL‐6 responses. Details relating to the mechanisms of sIL‐6R production will be provided, while the potential significance of sIL‐6R during the development of clinical conditions will be emphasized. We want to convey, therefore, that when thinking about the inflammatory capability of IL‐6, it is essential to consider not only the action of IL‐6 itself, but also the effect sIL‐6R may have on cellular processes.—Jones, S. A., Horiuchi, S., Topley, M. Yamamoto, N., Fuller, G. M. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 15, 43–58 (2001)