Not long ago, the term “RNAi”—short for “RNA interference”—became common to the vernacular of scientists and non-scientists alike as a huge potential step for basic scientific studies and new therapeutic approaches. This fundamental discovery by Craig Mello and Andy Fire garnered them a share of the 2006 Nobel Prize in Physiology and Medicine and availed a path to impede translation of desired eukaryotic mRNAs, and hence, to block production of their respective proteins. And while significant and promising advances have been made in RNAi research and therapeutic development, there are common obstacles to its use: the requirement for specific, efficient, and targeted small interfering RNA (siRNA) delivery to desired tissues; the potential adverse, off-target effects of treatment; and siRNA instability, immunoreactivity, and challenges to traversing anatomical barriers. And while RNAi has availed some fantastic new biological discoveries and bolstered some exciting potential disease therapies over the past couple of decades, some other exciting discoveries were being made in the mid- to late-2000s in a separate pathway that also functions to help ward off invading foreign genetic material, but in prokaryotes. This system was dubbed “CRISPR-Cas” (for “clustered regularly interspersed short palindromic repeats” – “CRISPR-associated protein”), and opened up an explosion of new research based on an unheard-of question: what if genomes could be edited directly? As it turns out, this was the case, and driven by CRISPR-Cas, many thousands of articles have been published in the past 10 years on this new fundamental biology and derivative biotechnological methods, from gene inactivation, genetic error correction, and innumerable synthetic biology advancements. But like RNAi, CRISPR-Cas also has its own Achilles’ heel(s) in how it functions and leads to some of the incidental errors and off-target damage it can cause. As described in a recent overview of a new development in CRISPR-Cas technology, conventional CRISPR-Cas suffers from these problems, due in part to the fact that its editing requires cleaving both strands of the DNA target, and that the DNA repair machinery of the cell must correct the damage that the enzyme complex creates; fixing this damage often results in the addition or removal of bases, and that does not lend to an overly precise process. But investigators at Harvard University have just published their variation on the CRISPR-Cas-based approach—called “prime editing”—which is a clever workaround that could significantly reduce the errors and damage that has thus far plagued the use of CRISPR-Cas. Rather than operating with a fully functional CRISPR-Cas complex, the group engineered the double-stranded-DNA-cutting Cas9 enzyme so that it could only nick a single DNA strand. And rather than using the usual “guide RNA” to merely target the complex to the desired site for editing, they implement a “prime editing guide RNA” (pegRNA) that both targets and is used as the template to directly edit the specific DNA site to become the desired sequence. How is it then possible to change the DNA sequence via an RNA intermediate? This is where the magic happens: they fused an engineered reverse transcriptase enzyme to the mutated Cas9 enzyme, and this reverse transcriptase uses the pegRNA itself as the template to lay down a desired new DNA sequence that replaces the former. This new edited sequence is “equilibrated” into the original single DNA strand, and following cleavage of the old sequence and ligation of the new sequence into that strand, the cellular DNA repair machinery is constrained to correct the opposite single strand of DNA to match the original that has been edited. It seems that smaller DNA sequences would be the ideal targets for this prime editing technology, and the accuracy of the reverse transcriptase and impediments caused by secondary structures that are involved could end up being barriers to its precision. Also, like RNAi and conventional CRISPR-Cas, successful delivery of its components into the desired tissues will be key: introducing a large RNA construct and cognate enzymes into the desired live cells will be no small feat. Nevertheless, with a whole slew of single-nucleotide diseases that beg a biotechnological cure, prime editing could be the solution to help science address them, just in the nick of time.