Addressing a fundamental limitation in CRISPR-Cas genome editing, researchers have developed new engineered Cas9 variants that nearly eliminate the need for a protospacer adjacent motif known as PAM. This motif is otherwise required for DNA-targeting CRISPR enzymes. According to the report, the novel Cas9 enzymes open up virtually the entire genome for targeting, with unprecedented accuracy. This drastically expands the potential of CRISPR-Cas systems, the authors say, something they showed by using their approach to correct mutations associated with human diseases located in previously "un-editable" regions of the genome. DNA-targeting CRISPR-associated enzymes find their targets by recognizing protospacer adjacent motif (PAM) sequences - short bits of genetic code that flag editable sections of DNA and serve as a binding signal for specific CRISPR-Cas nucleases. Without an adjacent, recognizable PAM sequence, a Cas enzyme will not recognize nor successfully attach to and cleave a desired section of DNA. While different Cas enzymes, including variants of the canonical Streptococcus pyogenes Cas9 (SpCas9), recognize different PAM sequences, much of the genome remains un-targetable for editing or more prone to generating off-target mutations. Thus, the PAM requirement represents a significant limiting barrier for applications that require high-resolution genome targeting. To address this limitation, Russell Walton and colleagues engineered new variants of the SpCas9 enzyme capable of targeting and editing sequences bearing a wider array of PAMs. Here, Walton et al. report on two significant variants: SpG, which is capable of targeting an expanded set of NGN PAMs, and a near-PAMless variant called SpRY. Collectively, SpG and SpRY enable unconstrained targeting using CRISPR-Cas9 nucleases across nearly the entire genome and with single base pair precision. Using SpRY, the authors were able to correct mutations associated with human diseases located in previously "un-editable" regions of the genome.