Retinoic acid inducible gene-I (RIG-I), named for the observation that its mRNA expression is highly upregulated in the progression of all-trans retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells, has been well documented as a pivotal virus-associated molecular pattern recognition receptor (PRR) responsible for triggering innate immunity. Upon recognizing viral RNA ligands, RIG-I experiences a series of programmed conformational changes and modifications that unleash its activity through the formation of complexes with various binding partners. Such partners include the mitochondria membrane-anchored protein IPS-1 (also named MAVS/VISA/Cardif) that activates both the IRF3/7 and NF-κB pathways. These partnerships and resulting pathway activations underlie the synthesis of type I interferon and other inflammatory factors. Recent studies have demonstrated that RIG-I is also involved in the regulation of basic cellular processes outside of innate immunity against viral infections, such as hematopoietic proliferation and differentiation, maintenance of leukemic stemness, and tumorigenesis of hepatocellular carcinoma. In this review, we will highlight recent studies leading up to the recognition that RIG-I performs an essential function as a tumor suppressor and try to reconcile this activity of RIG-I with its well-known role in protecting cells against viral infection.