The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co‐stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA‐binding proteins (RBPs), including Regnase‐1, Roquin, Tristetraprolin (TTP), and AU‐rich elements/poly(U)‐binding/degradation factor 1 (AUF1). Among these, Regnase‐1, also known as Zc3h12a and Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1), acts as an endoribonuclease responsible for the degradation of mRNAs involved in inflammatory responses. Conversely, the RBPs Roquin and TTP trigger exonucleolytic degradation of mRNAs by recruiting the CCR4‐NOT deadenylase complex. Regnase‐1 specifically recognizes stem‐loop structures present in 3′‐untranslated regions of cytokine mRNAs, and directly degrades the mRNAs in a translation‐ and ATP‐dependent RNA helicase upframeshift 1 (UPF1)‐dependent manner that is reminiscent of nonsense‐mediated decay. Regnase‐1 regulates the activation of innate and acquired immune cells, and is critical for maintaining immune homeostasis as well as preventing over‐activation of the immune system under inflammatory conditions. Furthermore, recent studies have revealed that Regnase‐1 and its family members are involved not only in immunity but also in various biological processes. In this article, I review molecular mechanisms of Regnase‐1‐mediated mRNA decay and its physiological roles. WIREs RNA 2018, 9:e1449. doi: 10.1002/wrna.1449 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease Regnase‐1/MCPIP1 is an endoribonuclease that degrades a set of mRNAs in a translation dependent manner by interacting with UPF1. Regnase‐1 recognizes mRNAs harboring a stem‐loop structure in the 3' untranslated region, and regulates various biological processes such as innate and adaptive immunity, as well as development, cancer and metabolism.