Mitogen-activated protein kinases (MAPKs), found in all eukaryotes, are signal-transducing enzymes that play a central role in a variety of biological processes. MAPK phosphatase has dual catalytic activity toward phosphotyrosine- and phosphothreonine-containing proteins, and is known to inactivate ERKs and JNKs/SAPKs, thus playing a crucial role in MAPK regulation. Although MAPK phosphatase has been implicated in a feedback loop that inactivates MAPKs after stimulation by mitogens and during the cellular response to stress, signaling pathways leading to MAPK phosphatase gene expression have not been fully elucidated. Recently, we have shown that a novel RNA-binding protein Rnc1 plays a crucial role in negative feedback regulation of MAPK signaling by stabilizing the mRNA of a MAPK phosphatase at the post-transcriptional level. One important aspect of our findings is that the increase in mRNA levels involves not only the transcriptional upregulation, but also the post-transcriptional gene regulation, especially the regulation of mRNA stability. Our discovery highlights a potential role and an emerging view of RNA-binding protein as a regulator of cell signaling and as a future target of drug discovery.