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Since the discovery of RNA-programmable nucleases from the prokaryotic adaptive immune system CRISPR-Cas, these proteins have seen rapid and widespread adoption for biotechnological and clinical research. A recently discovered system, CRISPR-Cas13, uses CRISPR RNA guides to target RNA. Interestingly, RNA targeting by Cas13 results in cleavage of both target RNA and bystander RNA. This feature has been used to develop innovative diagnostic tools for the detection of specific RNAs. Unlike in vitro detection of RNA using collateral RNA cleavage, however, initial studies of mammalian cells only revealed highly specific target RNA-knockdown activity. Although these findings have been confirmed subsequently, several recent publications do report Cas13-mediated toxicity and collateral RNA cleavage when using Cas13 in eukaryotes. Here, we review these conflicting observations and discuss its potential molecular basis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)