CRISPR is becoming an indispensable tool in biological research. Originally known as the bacterial immune system against viruses, the programmable Cas9 enzyme is now revolutionizing medical research, biotechnology, and agriculture. CRISPR-Cas9 is no longer just a gene-editing tool; applications of catalytically impaired inactive Cas9, including gene regulation, epigenetic editing, chromatin engineering, and imaging, now exceed the gene-editing functionality of wild-type Cas9. This review presents a brief history of gene-editing tools and describes the wide range of CRISPR-based genome-targeting tools. It concludes with future directions and the broader impact of CRISPR technologies. Great inventions are often seen as a series of lucky coincidences, but a closer look reveals that true serendipity is rare in molecular biology. Groundbreaking scientific advancements are built on decades of combined efforts. Even so-called serendipitous discoveries come from careful experiments by inquisitive researchers. The genome-editing technologies and CRISPR tools have reached an exciting stage through years of basic science research. This review will present the brief history and key developments in genome editing and major genome-engineering tools, with a focus on CRISPR technology. The application areas of CRISPR technology extending beyond genome editing, such as targeted gene regulation, epigenetic modulation, chromatin manipulation, and live cell chromatin imaging, will be emphasized. Finally, it will briefly discuss current and future impacts of these tools in science, medicine, and biotechnology. The history of genome-editing efforts began with the discovery of restriction enzymes in the late 1970s, which fueled the era of recombinant DNA technology. The ability to manipulate DNA in test tubes was a turning point. However, the ability to precisely alter DNA in living eukaryotic cells came later. Key developments in the mid to late 1980s included initial targeted gene disruption studies in eukaryotic yeast and breakthrough work by Capecchi and Smithies in mammalian cells. Their studies demonstrated that mammalian cells could incorporate exogenous DNA into their genome through homologous recombination. However, this approach had limitations, including low integration rates and random integration into undesired genomic loci. Researchers sought alternative approaches to overcome these limitations. One breakthrough was the realization that introducing a double-strand break (DSB) at a target site significantly increased the frequency of targeted gene integration. This led to the development of targeted nucleases, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). These tools allowed for more precise genome editing. However, the difficulty in cloning and protein engineering ZFNs and TALENs limited their adoption. CRISPR has revolutionized the field due to its robustness and flexibility. The CRISPR gene-editing technology is composed of an endonuclease protein whose DNA-targetCRISPR is becoming an indispensable tool in biological research. Originally known as the bacterial immune system against viruses, the programmable Cas9 enzyme is now revolutionizing medical research, biotechnology, and agriculture. CRISPR-Cas9 is no longer just a gene-editing tool; applications of catalytically impaired inactive Cas9, including gene regulation, epigenetic editing, chromatin engineering, and imaging, now exceed the gene-editing functionality of wild-type Cas9. This review presents a brief history of gene-editing tools and describes the wide range of CRISPR-based genome-targeting tools. It concludes with future directions and the broader impact of CRISPR technologies. Great inventions are often seen as a series of lucky coincidences, but a closer look reveals that true serendipity is rare in molecular biology. Groundbreaking scientific advancements are built on decades of combined efforts. Even so-called serendipitous discoveries come from careful experiments by inquisitive researchers. The genome-editing technologies and CRISPR tools have reached an exciting stage through years of basic science research. This review will present the brief history and key developments in genome editing and major genome-engineering tools, with a focus on CRISPR technology. The application areas of CRISPR technology extending beyond genome editing, such as targeted gene regulation, epigenetic modulation, chromatin manipulation, and live cell chromatin imaging, will be emphasized. Finally, it will briefly discuss current and future impacts of these tools in science, medicine, and biotechnology. The history of genome-editing efforts began with the discovery of restriction enzymes in the late 1970s, which fueled the era of recombinant DNA technology. The ability to manipulate DNA in test tubes was a turning point. However, the ability to precisely alter DNA in living eukaryotic cells came later. Key developments in the mid to late 1980s included initial targeted gene disruption studies in eukaryotic yeast and breakthrough work by Capecchi and Smithies in mammalian cells. Their studies demonstrated that mammalian cells could incorporate exogenous DNA into their genome through homologous recombination. However, this approach had limitations, including low integration rates and random integration into undesired genomic loci. Researchers sought alternative approaches to overcome these limitations. One breakthrough was the realization that introducing a double-strand break (DSB) at a target site significantly increased the frequency of targeted gene integration. This led to the development of targeted nucleases, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). These tools allowed for more precise genome editing. However, the difficulty in cloning and protein engineering ZFNs and TALENs limited their adoption. CRISPR has revolutionized the field due to its robustness and flexibility. The CRISPR gene-editing technology is composed of an endonuclease protein whose DNA-target