Interferons (IFNs) comprise a family of secreted proteins that function as important biologic response modifiers in vertebrates. Interferons are produced in response to viral and other microbial infections, they bind to specific receptors on the surface of target cells, and they induce rapid activation of gene transcription. Interferon-stimulated genes modulate many biologic effects of IFNs. Characterization of the molecular mechanisms of IFN-induced gene activation led to the discovery of two distinct families of proteins, known as the Janus family kinases (Jaks) and the signal transducers and activators of transcription (Stats). These signaling proteins transduce intracellular signals from IFN receptors to the nucleus and activate transcription of IFN-stimulated genes. Subsequent studies have shown that many cytokines, hormones, and growth factors signal their target cells through the Jak-Stat signal transduction pathway. Significant molecular cross-talk between Jaks and Stats recruited to IFN receptors in response to IFN-alpha stimulation and other signaling pathways may be involved in the etiology of some of the side effects associated with IFN-alpha therapy.