Organisms from every branch of life have evolved defenses against the viral parasites that infect them. For many bacteria and archaea, resistance to viruses is provided by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). This system of proteins and RNAs provides sequence-specific targeting against foreign genetic elements like viruses. CRISPR loci are a cluster of repeats separated by short ‘‘spacer’’ sequences derived from prokaryotic viruses and plasmids that determine the targets of the host’s CRISPR-Cas immune response against its invaders. For type I and II CRISPR-Cas systems, single-nucleotide mutations in the seed or proto- spacer adjacent motif (PAM) of the target sequence cause immune failure and allow viral escape. This is overcome by the acquisition of multiple spacers that target the same invader. Here we show that targeting by the Staphylococcus epidermidis type III-A CRISPR-Cas system does not require PAM or seed sequences, and thus prevents viral escape via single-nucleotide substitutions. Instead, viral escapers can only arise through complete target deletion. Our work shows that, as opposed to type I and II systems, the relaxed specificity of type III CRISPR-Cas targeting provides robust immune responses that can lead to viral extinction with a single spacer targeting an essential phage sequence.Studies on the Type II system show that an infected population of bacteria will pick up a diverse spread of spacers from across the phage genome. In liquid culture, where cells constantly mix, a phage mutant can overcome the immunity of one spacer to kill the host, but upon infection of a neighboring cell they will encounter a different spacer and stop propagating. Whether and how this fail-safe mechanism works when the population is immobilized in solid media is not known. Here we show that when grown in top agar, a subset of cells within a single colony will acquire additional spacers that help combat resistant phage. This arms race between the host and virus changes the physical structure of the colony, as seen through segmentation of different sub-populations. Our work reveals how the dynamics of the CRISPR immune response critically depend on the ecology and interactions of the bacterial host.