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Simple Summary Approaches to manipulate the genome of an organism, both selectively and accurately, are powerful techniques that can influence research practice, with extensive application to agriculture and medicine, including the ability to impact disease risk or onset. In this review article, we highlight the advances, made over several decades, on the procedures and capacities to facilitate genome editing, manifest with the discovery, characterization, and optimization of the mechanism for processing of clustered regularly interspaced short palindromic repeat sequences (CRISPR). The editing molecules in the CRISPR gene modification system behave as molecular scissors, cutting DNA at specific genetic locations. First identified as a natural defense mechanism in bacteria, the CRISPR system has now been extensively modified for use in almost all mammalian cells. In describing each CRISPR mechanistic class, we acknowledge the differences and positive attributes each class has to offer to support editing that allows the creation of gene knockouts, knock-ins, gene tagging, insertions, deletions, and point mutations. Further, we discuss how these editing strategies have shaped the field of DNA repair. Specifically, we provide examples of the utility of CRISPR approaches in furthering our understanding of two of the major DNA repair pathways, namely mismatch repair and base excision repair. Abstract The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.