Inflammation progresses by the action of pro-inflammatory cytokines, including interleukin-1 (IL-1), the tumor necrosis factor (TNF), gamma-interferon (IFNgamma), IL-12, IL-18, and the granulocyte-macrophage colony-stimulating factor, and is resolved by anti-inflammatory cytokines such as IL-4, IL-10, IL-13, IFNalpha, and the transforming growth factor (TGF)beta. The intracellular signal transduction pathways of these cytokines have been studied extensively, and these pathways ultimately activate transcription factors, such as NF-kappaB, Smad, and STATs. Recently, the negative-feedback regulation of these pathways has been identified. In this review, we provide examples of the relationship between cytokine signal transduction, negative-signal regulation, and inflammatory disease models. Furthermore, we illustrate several approaches for treating inflammatory diseases by modulating extracellular and intracellular signaling pathways.