Interferons (IFNs) are a family of small regulatory glycoproteins that play a central role in the defense against viral infections. Although IFNs have been initially discovered as antiviral factors, today they are known as an integral part of the cytokine network that affect a wide range of biological processes. IFNs exert their pleiotropic effects through their multisubunit cell surface receptors in a species specific manner that is believed to be controlled at the receptor and the post-receptor levels. Although IFN-mediated signaling and transcription activation of cellular gene expression is currently best understood in the context of the JAK-STAT signal transduction, additional IFNs signaling pathways may also act in certain conditions. The Janus family of tyrosine kinase (JAK) enzymes and two families of transcriptional regulators, signal transducer and activator of transcription (STATS) and IFN regulatory factors (IRFs), are the principal components of the JAK-STAT pathway. Overlapping subsets of JAKS are involved in signaling by type I (IFN- α/ß) and type II (IFN-γ IFNs, indicating that the receptor subunits confer specificity for activating particular JAK family members. A considerable cross talk can exist between separate signaling pathways. The emergence of new tools and approaches for study of IFNs signaling has been an exercise in coming to respect the level of complexity of IFNs system. For many years, IFNs have been satisfactorily used in many clinical trials. However, their serious side effects remain as the major concern in clinical use of IFNs. A better understanding of the exact mechanism involved in IFNs signaling pathways and the structure-function relationships of the IFNs system components will allow researchers to improve and expand the therapeutic potential of these naturally occurring molecules. IFNs actions are mediated through multiple signaling pathways. However, due to the space limitation, this review will focus primarily on the IFNs-mediated JAK-STAT pathway.