The growth and differentiation of cells that make up multicellular entities such as the blood and immune systems are under the control of glycoprotein mediators known as cytokines. These cytokines bind to membrane receptors on the cell surface and initiate a signaling cascade that ends with the transcription of specific sets of genes within the cell nucleus. Although knowledge is accumulating concerning the intracellular signal pathways that are activated by cytokines, little is known about inhibition of cytokine signals. This review will focus on the negative regulation of the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway by proteins related to STAT-induced STAT inhibitor-1 (SSI-1).