Proinflammatory cytokines are produced by innate immune cells upon sensing of pathogens by Toll-like receptors (TLRs). The expression of proinflammatory cytokines is controlled at the transcriptional and posttranscriptional levels. Posttranscriptional control of cytokine mRNAs is critical for preventing excess and persistent production of cytokines by degrading them via a set of RNA binding proteins (RBPs) recognizing cis-elements present in the mRNA 3’-untranslated region. Among RBPs, Roquin recognizes stem-loop structures present in mRNAs encoding inflammatory proteins and degrades them by recruiting a CCR4-NOT deadenylase complex to its target mRNAs. Roquin-mutant mice spontaneously develop autoimmunity by elevated expression of ICOS on T cells and enhanced production of TNF in innate immune cells. We identified Regnase-1 (also known as Zc3h12a) as an endonuclease essential for degradation of inflammation-related mRNAs such as Il6 induced by TLR stimuli in innate immune cells. Regnase-1 is also critical for suppressing activation of T cells and maintenance of immune homeostasis in mice. We found that Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure. However, Regnase-1 and Roquin function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically degrades translationally active mRNAs depending on UPF1, a helicase essential for the nonsense-mediated mRNA decay. Regnase-1 and Roquin control early and late phase of inflammation, respectively. Interestingly, Regnase-1 recognizes inflammatory mRNAs undergoing pioneer rounds of translation, which is triggered by the phosphorylation of UPF1 by a kinase SMG1. Taken together, our findings reveal that differential regulation of immune-related mRNAs by two RNA binding proteins, Regnase-1 and Roquin, depends on their translation status and enables elaborate control of inflammation.