Many infectious agents elicit a type I interferon response but, until recently, the molecular details that coordinate interferon (IFN)-alpha and -beta expression during infection were unknown. Innate immune pattern recognition receptors, including Toll-like receptors and cytoplasmic RNA helicases such as retinoic acid-inducible gene, that sense viral nucleic acids have been discovered. Using distinct mechanisms, these receptors trigger cellular signaling pathways, culminating in the activation of interferon regulatory factors that transcriptionally induce IFN-alpha and IFN-beta genes.