The immune response system has a central role in eliminating detrimental factors by frequently launching inflammatory responses towards pathogen infection and inner danger signal outbreak. Acute and chronic inflammatory responses are critical determinants for consequences of inflammatory arthritis and nephritis, in which cytokine network systems were inevitably involved. Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, interferons, and tumor necrosis factor set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase/signal transducer and activator of transcription, the nuclear factor kappa-light-chain-enhancer of activated B cells, the mitogen-activated protein kinase and the Phosphatidylinositol-3'-kinases pathways have all been intensively studied, and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Therefore, challenges in autoimmune arthritis and nephritis include continuing to improve the advances in pathogenesis and molecular biology, and novel therapeutic options.