RNA-virus infection activates retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), which causes a strong host antiviral immune response by inducing type I interferons and proinflammatory cytokines. In this review, the authors give an overview about the antiviral mechanisms of RLR signaling. They summarize how the RLR signaling cascade is strictly controlled by host regulatory mechanisms, and how RLRs participate in diseases, including SARS-CoV-2, and how SNPs or mutations in RLRs and antibodies against RLR lead to autoinflammatory diseases.