CRISPR (clustered regularly interspaced short palindromic repeats) loci are composed of short DNA repeats interspaced by short unique DNA sequences (spacers). CRISPRs are often allied with a set of proteins (Cas - CRISPR associated) that together form a microbial immune system. Since its first description in Escherichia coli in 1987, CRISPR-Cas has been found in most archaea and about half of bacteria. Such is the case with dairy starter bacteria Streptococcus thermophilus, where up to 4 unique CRISPR-Cas loci have been in a single strain and where the biological activity of the immunity was first described. As with earlier applications, the diversity and uniqueness of the CRISPR spacer content was extremely useful for strain typing. Upon closer investigation, it was observed that the spacer sequences were homologous to extrachromosomal elements; namely phage DNA. Subsequently, a direct correlation was established showing that a spacer with sequence identity to a given phage can direct Cas proteins to interfere with that phage’s ability to propagate within the host – phage resistance. The ensuing studies of the interference mechanism of action and enzymology gave rise to what is commonly known today as CRISPR-Cas9 genome editing; a powerful tool for targeted genomic modifications and the object of much attention in the scientific community. In its natural state, the native S. thermophilus CRISPR-Cas system has proven to be a highly effective defense against virulent phage; a persistent issue in industrial dairy fermentations. Exposing S. thermophilus to a virulent phage naturally induces incorporation of a new spacer into the CRISPR array, conferring resistance to the virulent phage. The adaptation process is such that the level of phage resistance increases by incorporation of additional unique spacer sequences to a given phage, expands the range of inhibition by spacer addition from unrelated phages, or both following an iterative process of phage challenge and strain selection. When performed under controlled conditions, secondary mutations are virtually non-existent, therefore preserving the physiological properties of highly functional unique strains.