Interestingly, recent work has established that MyD88 / Trif / cells are capable of responding to nucleic acid ligands via cytosolic immunosurveillance pathways. Cytosolic RNA appears to be sensed by two RNA helicase-containing proteins, RIG-I and Mda5 (Yoneyama et al., 2004) . Interestingly, RIG-I and Mda5 do not perform redundant functions and appear to respond to distinct classes of viruses (Gitlin et al., 2006; Hornung et al., 2006; Kato et al., 2006; Pichlmair et al., 2006; . Signaling by RIG-I and Mda5 requires a common adaptor molecule called MAVS (also known as IPS-1, Cardif, or VISA; Kawai et al., 2005; Meylan et al., 2005; Seth et al., 2005; Xu et al., 2005; Sun et al., 2006) . MAVS recruits the TBK1 kinase that phosphorylates and activates the IRF3 transcription factor. Other transcription factors such as ATF2/c-Jun and NK-B form a coordinated DNA-bound complex with IRF3, and are together required for robust activation of the IFN- promoter (Maniatis et al., 1998; Panne, 2008) .