With the rapid developments in biotechnology that have occurred over the last decade, the application of immunotherapy has been expanded to encompass many different conditions with increasing frequency of use. For example, exogenous therapy with cytokines has been widely used to treat chronic viral hepatitis and several different malignancies (1–13)(Table 1). This approach has led to an improvement in the prognosis of many malignancies, but has also been associated with some unexpected side effects. The antitumor properties of interleukin-2 (IL-2), with the additional antiviral properties of interferon-(IFN), were clearly the motivating factors for applying cytokine manipulation to treat conditions that have an otherwise dismal prognostic outlook. Indeed, immunotherapy has led to improved survival rates for many malignancies and increased remission rates in patients with chronic viral hepatitis (1, 2). However, trials in the 1980s showed that autoimmune thyroid disease could be induced with exogenous cytokine therapy (14). There have since been a number of studies and numerous anecdotal reports describing various autoimmune manifestations secondary to exogenous cytokine immunostimulation. The potential induction of autoimmunity by a host of more conventional drugs (eg, sulfasalazine, isoniazid, hydralazine) is well established (15). This review attempts to summarize the literature to date and explore possible mechanisms of autoimmune disease induction. The aim is to provide the reader with a summary that may be used to help guide one’s practice when called upon to advise or manage a patient with an autoimmune rheumatic manifestation who is undergoing immunotherapy. We also explore how we can harness information gleaned from immunotherapy trials to confirm, or indeed expand, our laboratory and clinically based knowledge concerning the role cytokines play in the etiopathogenesis of autoimmunity. We will particularly focus on the two most commonly used cytokines, IFN and IL-2; however, we also discuss published reports of rheumatic disease associated with other therapeutic cytokines such as IFN, IFN, and colonystimulating factor. Though treatment of rheumatoid arthritis (RA) with anti–tumor necrosis factor(anti-TNF) monoclonal antibodies is not, strictly speaking,“cytokine therapy,” autoantibody production de novo has been linked to anti-TNF therapy and is thus briefly discussed. The clinical indications for these cytokines (16–18) are listed in Table 1. Although autoimmune thyroid disease is the most common autoimmune manifestation associated with immunotherapy and indeed should not be overlooked in the clinical setting, we focus herein mainly on autoimmune rheumatic manifestations.