More than a half a century ago, interferons (IFN) were identified as antiviral cytokines. Since that discovery, IFN have been in the forefront of basic and clinical cytokine research. The pleiotropic nature of these cytokines continues to engage a large number of investigators to define their actions further. IFN paved the way for discovery of Janus tyrosine kinase (JAK)-signal transducing activators of transcription (STAT) pathways. A number of important tumor suppressive pathways are controlled by IFN. Several infectious pathogens counteract IFN-induced signaling pathways. Recent studies indicate that IFN activate several new protein kinases, including the MAP kinase family, and downstream transcription factors. This review not only details the established IFN signaling paradigms but also provides insights into emerging alternate signaling pathways and mechanisms of pathogen-induced signaling interference.