Interleukin-1 receptor antagonist (IL-1ra) has been shown to play a crucial role in the prevention of various inflammatory diseases. There is also convincing evidence that IL-1ra is able to counteract inflammatory effects of IL-1 members implicated in insulin resistance and diabetes. However, the use of knock-out animal models provides evidence to the contrary and the role of IL-1ra in obesity-linked anomalies remains controversial. This minireview gets an insight into recent findings on the implication of IL-1ra and its gene polymorphism in diabetes and obesity, discusses the potential dual effects of IL-1ra observed in different models, and comments on future directions.