The molecular cloning and biological analyses of cytokines have led us to a general understanding of their pleiotropism and redundancy. These features have been ascribed to the composition of cytokine receptor complexes, which include a signal-transducing receptor subunit that is used by all members of a cytokine family and a binding subunit that is specific for each cytokine. Even though a given cytokine uses the same receptor complex when binding to various cell types, the cytokine elicits quite specific and distinct biological responses in different types of cells. Even in the same type of cell, the responses to a given cytokine could vary depending on the location of the cell and the condition of its microenvironment. Important mediators for the main cytokine signal-transduction pathway are the Janus kinases (Jaks) and signal transducer and activator of transcription (STATs). Selective usage of members of the Jak and STAT families by a given cytokine receptor is partly responsible for the specificity of cytokine action. In addition to the Jak–STAT pathway, a cytokine receptor complex can simultaneously operate multiple signal-transduction pathways, which usually express contradictory properties. These contradictory signals from a single cytokine are orchestrated to evoke a unified biological response in the cell. Here we discuss the molecular mechanisms that regulate how the cell specificity of cytokine signals is regulated, especially focusing on the IL-6/gp130 system.