In the past few years, several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote beta-cell destruction and alter insulin sensitivity. The effects of IL-1 are likely to be counteracted by IL-1 receptor antagonist protein (IL-1ra), as suggested by interventional studies in patients with T2DM who were treated with a recombinant form of this protein. However, studies in IL-1ra-deficient mice provided controversial results on the exact effect of the IL-1 signaling pathway on insulin secretion, insulin sensitivity and accumulation of adipose tissue. Likewise, IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and beta-cell function.