Chronic low-grade inflammation has been well recognized as a key feature of obesity that is correlated with insulin resistance and type 2 diabetes. Among the adipose-secreted factors (adipokines), the inflammatory regulator interleukin-6 (IL-6) has emerged as one of the potential mediators that link obesity-derived chronic inflammation with insulin resistance. Adipose tissue contributes to up to 35% of circulating IL-6, the systemic effects of which have been best demonstrated in the liver, where a STAT3-SOCS-3 pathway mediates IL-6 impairment of insulin actions. However, this cytokine displays pleiotropic functions in a tissue-specific and physiological context-dependent manner. In contrast to its role in liver, IL-6 is believed to be beneficial for insulin-regulated glucose metabolism in muscle. Furthermore, the effects of the cytokine are seemingly influenced by whether it is present acutely or chronically; the latter is the setting associated with insulin resistance. Herein we review the in vivo and in vitro studies that have examined the role of IL-6 in insulin signaling and glucose metabolism in the insulin target tissues: liver, adipose, and skeletal muscle.