The interleukin-1 receptor antagonist (IL-1ra) is unusual in that it is the only known naturally occurring, cytokine receptor antagonist with no apparent agonist function. Over the last 5 years, since the cloning of the IL-1ra cDNA sequence, there has been intensive research on the genetics, regulation, and potential therapeutic value of this protein. The later discovery of a second form of IL-1ra in 1991 has complicated the picture. Whereas the originally described IL-1ra is predominantly glycosylated and secreted (sIL-1ra), the alternative isoform is unglycosylated and intracellular (icIL-1ra). Although the biological roles of the two forms are still open to question, IL-1ra is likely to be of great importance in the pathogenesis of both acute and chronic inflammatory diseases. A large body of evidence for this conclusion has come from animal models of inflammatory disease that respond well to administration of exogenous IL-1ra. A role for recombinant IL-1ra in the management of human disease is still under investigation. The two forms of IL-1ra are encoded by a single gene by alternative usage of two first exons. Expression of sIL-1ra and icIl-1ra is regulated by two promoters. In this review I explore the genetics of the gene encoding IL-1ra (IL-1RN) and the mechanisms of IL-1ra gene activation to produce sIL-1ra and icIL-1ra. Also, possible biological roles for these immunomodulators in health and disease are discussed.