• The core feature of CRISPR-Cas systems is the use of RNA-guided Cas nucleases that use a short RNA to locate and cleave complementary nucleic acids.
• Recent studies uncovered features that add substantial complexity to this central mechanism.
• Upon crRNA-guided recognition of complementary nucleic acids, many CRISPR-Cas systems also degrade nontarget RNA or ssDNA.
• The RNA-guided recognition of target RNA molecules triggers the production of cyclic oligoadenylate; a secondary messenger that activates the nonspecific degradation of RNA during type III CRISPR-Cas immunity.
• Many inhibitors of Cas nucleases have been found in phage genomes, which require the cooperative infection of viruses to gradually suppress the CRISPR-Cas immune response.

Clustered regularly interspaced short palindromic repeats (CRISPR) loci and their associated ( cas) genes provide protection against invading phages and plasmids in prokaryotes. Typically, short sequences are captured from the genome of the invader, integrated into the CRISPR locus, and transcribed into short RNAs that direct RNA-guided Cas nucleases to the nucleic acids of the invader for their degradation. Recent work in the field has revealed unexpected features of the CRISPR-Cas mechanism: (i) collateral, nonspecific, cleavage of host nucleic acids; (ii) secondary messengers that amplify the immune response; and (iii) immunosuppression of CRISPR targeting by phage-encoded inhibitors. Here, we review these new and exciting findings.