Metazoan cells secrete small proteins termed cytokines that execute a variety of biological functions essential for the survival of organisms. Binding of cytokines that belong to the hematopoietin- or interferon-family, to their cognate receptors on the surface of target cells, induces receptor aggregation, which in turn sequentially triggers tyrosine-phosphorylation-dependent activation of receptor-associated Janus-family tyrosine kinases (JAKs), receptors, and signal transducers and activators of transcription (STATs). Phosphorylated STATs form dimers that migrate to the nucleus, bind to cognate enhancer elements and activate transcription of target genes. Each cytokine activates a specific set of genes to execute its biological functions with a certain degree of redundancy. Cytokine signals are, in general, transient in nature. Therefore, under normal physiological conditions, initiation and attenuation of cytokine signals are tightly controlled via multiple cellular and molecular mechanisms. Aberrant activation of cytokine signaling pathways is, however, found under a variety of patho-physiological conditions including cancer and immune diseases.