Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.