CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins) adaptive immune systems defend microbes against foreign nucleic acids via RNA-guided endonucleases. These systems are divided into two classes: class 1 systems utilize multiple Cas proteins and CRISPR RNA (crRNA) to form an effector complex while class 2 systems employ a large, single effector with crRNA to mediate interference. Cas6 family endoribonucleases are typically found within types I and III CRISPR-Cas systems and are metal-independent nucleases that catalyze RNA cleavage via a mechanism involving a 2'-3' cyclic intermediate. They share a common ferredoxin or RNA recognition motif (RRM) fold, and they recognize and excise CRISPR repeat RNAs that vary widely in primary and secondary structures. Cas6 is also found in the rare type IV system that includes rudimentary CRISPR-cas loci lacking the adaptation module.