Dynamic changes in gene expression are key factors in the development and activation of immune cells. RNA metabolism is one of the critical steps for the control of gene expression. Together with transcriptional regulation, mRNA decay by specific ribonucleases (RNases) plays a vital role in shaping gene expression. In addition to the canonical exoribonuclease-mediated mRNA degradation through the recognition of cis-elements in mRNA 3' untranslated regions by RNA-binding proteins (RBPs), endoribonucleases are involved in the control of mRNAs in immune cells. In this review, we gleam insights on how Regnase-1, an endoribonuclease necessary for regulating immune cell activation and maintenance of immune homeostasis, degrades RNAs involved in immune cell activation. Additionally, we provide insights on recent studies which uncover the role of Regnase-1-related RNases, including Regnase-2, Regnase-3, and Regnase-4, as well as N4BP1 and KHNYN, in immune regulation and antiviral immunity. As the dysregulation of immune mRNA decay leads to pathologies such as autoimmune diseases or impaired activation of immune responses, RNases are deemed as essential components of regulatory feedback mechanisms that modulate inflammation. Given the critical role of RNases in autoimmunity, RNases can be perceived as emerging targets in the development of novel therapeutics.