The immune response is replete with feedback control at many levels. These protective circuits are even functional within the arthritic joint, tempering disease to varying extents. An optimal therapy would inhibit autoimmune processes while maintaining protective circuitry. However, many of the cells and proteins that serve as important mediators of disease progression also play an active role in these protective circuits. The hypothesis considered in this review is that the inadvertent inhibition of protective circuitry adversely affects efficacy. Conversely, if therapeutics can be designed, which avoid inhibiting known regulatory circuits, efficacy will be improved. Understanding where these processes share signaling molecules will be crucial to the development of the next generation of therapeutics. This review discusses three well-defined signal transduction cascades; IL-2, IFNγ and TNF-α, and demonstrate within two cell types, T cells and macrophages, how these cytokines may contribute both to protection and to disease progression.