Antiviral innate immunity is triggered by sensing viral nucleic acids. RIG-I (retinoic acid-inducible gene-I) is an intracellular molecule that responds to viral nucleic acids and activates downstream signaling, resulting in the induction of members of the type I interferon (IFN) family, which are regarded among the most important effectors of the innate immune system. Although RIG-I is expressed ubiquitously in the cytoplasm, its levels are subject to transcriptional and post-transcriptional regulation. RIG-I belongs to the IFN-stimulated gene (ISG) family, but certain cells regulate its expression through IFN-independent mechanisms. Several lines of evidence indicate that deregulated RIG-I signaling is associated with autoimmune disorders. Further studies suggest that RIG-I has functions in addition to those directly related to its role in RNA sensing and host defense. We have much to learn and discover regarding this interesting cytoplasmic sensor so that we can capitalize on its properties for the treatment of viral infections, immune disorders, cancer, and perhaps other conditions.