Retinoic acid–inducible gene I–like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.