The genes for IL-3, IL-4, IL-5, IL-9, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are known to be clustered on human chromosome 5q and on mouse chromosome 11. IL-2 and interferon gamma (IFN-γ) genes are located on separate chromosomes. It is well known that upon stimulation by antigen presentation, T_H1 and T_H2 subsets of T helper cells start to transcribe distinct sets of cytokine genes. Thus mechanisms should exist that transmit extracellular signals into the nucleus, thereby coordinately turning on transcriptional machinery in cell type-specific manners. Several different mechanisms exist in which specific as well as coordinated expression of cytokines are regulated at the transcriptional level. These include (1) regulation by proximalcis-elements, to which specific transcription factors bind, (2) regulation by distal cis-elements, such as enhancers or locus controlling elements, especially those located several kilobases away from the target gene, and (3) enhancement of transcription by viral trans-activators in a pathologic state. In this article, we review the recent studies on the above issues, with particular emphasis on our own results that support the presence of different modes of control mechanisms. We also discuss the possible approaches to the thorough understanding of the coordinated and specific regulation of cytokines. (J Allergy Clin Immunol 1996;98:174-82.)