AbstractEndonuclease cleavage was one of the first identified mechanisms of mRNA decay but until recently it was thought to play a minor role to the better‐known processes of deadenylation, decapping, and exonuclease‐catalyzed decay. Most of the early examples of endonuclease decay came from studies of a particular mRNA whose turnover changed in response to hormone, cytokine, developmental, or nutritional stimuli. Only a few of these examples of endonuclease‐mediated mRNA decay progressed to the point where the enzyme responsible for the initiating event was identified and studied in detail. The discovery of microRNAs and RISC‐catalyzed endonuclease cleavage followed by the identification of PIN (pilT N‐terminal) domains that impart endonuclease activity to a number of the proteins involved in mRNA decay has led to a resurgence of interest in endonuclease‐mediated mRNA decay. PIN domains show no substrate selectivity and their involvement in a number of decay pathways highlights a recurring theme that the context in which an endonuclease function is a primary factor in determining whether any given mRNA will be targeted for decay by this or the default exonuclease‐mediated decay processes. WIREs RNA 2011 2 582–600 DOI: 10.1002/wrna.78This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability