G-quadruplexes are four-stranded DNA structures found in gene promoters and are emerging as potential therapeutic targets in oncology. These structures can stabilize oncogene transcription, offering a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties that make them druggable, and their structural diversity suggests high selectivity. The article discusses the evidence for G-quadruplexes in gene promoters, their potential as therapeutic targets, and progress in developing small-molecule ligands to target them. DNA was the first target for anticancer drugs, but interest waned with the rise of new molecular targets like kinases. The discovery of G-quadruplexes in telomeres marked a new era for DNA-targeted therapeutics. Telomerase, which maintains telomeres, is selectively expressed in cancers, making it a promising target. Research on telomeric G-quadruplexes has shown their biological and therapeutic significance, and their potential as drug targets continues to be explored. G-quadruplexes are found in the promoters of many genes involved in cell signaling, including oncogenes like MYC, KRAS, and KIT. These genes are important therapeutic targets, and their promoters contain G-quadruplex-forming sequences. Studies have shown that small molecules can target these sequences, leading to transcriptional repression and potential anticancer effects. For example, TMPyP4 stabilizes the MYC G-quadruplex, inhibiting MYC expression. Similarly, quarfloxin, a first-in-class G-quadruplex-interacting compound, has shown promise in clinical trials, though it was withdrawn due to bioavailability issues. The article highlights the structural characteristics of promoter G-quadruplexes, including their formation from single, double, or four-stranded DNA. These structures are dynamic and can form multiple arrangements. Studies have identified G-quadruplexes in genes like MYC, BCL-2, VEGF, and KRAS. These structures are often found in regions proximal to transcription start sites and are associated with gene regulation. Genome-wide analyses have shown that G-quadruplex-forming sequences are prevalent in the human genome, particularly in promoter regions of protein-coding genes. These sequences are enriched in regions near transcription start sites and are associated with gene expression. Computational studies have identified G-quadruplex motifs in various genomes, and their presence is linked to gene function and regulation. The therapeutic potential of targeting G-quadruplexes is supported by studies showing that small molecules can modulate gene expression by stabilizing or destabilizing these structures. For example, quarfloxin inhibits Pol I transcription and displaces nucleolin from the nucleolus, leading to cell-cycle arrest. However, challenges remain in developing selective and effective G-quadruplex-targeting drugs, particularly due to the complexity of G-quadrupG-quadruplexes are four-stranded DNA structures found in gene promoters and are emerging as potential therapeutic targets in oncology. These structures can stabilize oncogene transcription, offering a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties that make them druggable, and their structural diversity suggests high selectivity. The article discusses the evidence for G-quadruplexes in gene promoters, their potential as therapeutic targets, and progress in developing small-molecule ligands to target them. DNA was the first target for anticancer drugs, but interest waned with the rise of new molecular targets like kinases. The discovery of G-quadruplexes in telomeres marked a new era for DNA-targeted therapeutics. Telomerase, which maintains telomeres, is selectively expressed in cancers, making it a promising target. Research on telomeric G-quadruplexes has shown their biological and therapeutic significance, and their potential as drug targets continues to be explored. G-quadruplexes are found in the promoters of many genes involved in cell signaling, including oncogenes like MYC, KRAS, and KIT. These genes are important therapeutic targets, and their promoters contain G-quadruplex-forming sequences. Studies have shown that small molecules can target these sequences, leading to transcriptional repression and potential anticancer effects. For example, TMPyP4 stabilizes the MYC G-quadruplex, inhibiting MYC expression. Similarly, quarfloxin, a first-in-class G-quadruplex-interacting compound, has shown promise in clinical trials, though it was withdrawn due to bioavailability issues. The article highlights the structural characteristics of promoter G-quadruplexes, including their formation from single, double, or four-stranded DNA. These structures are dynamic and can form multiple arrangements. Studies have identified G-quadruplexes in genes like MYC, BCL-2, VEGF, and KRAS. These structures are often found in regions proximal to transcription start sites and are associated with gene regulation. Genome-wide analyses have shown that G-quadruplex-forming sequences are prevalent in the human genome, particularly in promoter regions of protein-coding genes. These sequences are enriched in regions near transcription start sites and are associated with gene expression. Computational studies have identified G-quadruplex motifs in various genomes, and their presence is linked to gene function and regulation. The therapeutic potential of targeting G-quadruplexes is supported by studies showing that small molecules can modulate gene expression by stabilizing or destabilizing these structures. For example, quarfloxin inhibits Pol I transcription and displaces nucleolin from the nucleolus, leading to cell-cycle arrest. However, challenges remain in developing selective and effective G-quadruplex-targeting drugs, particularly due to the complexity of G-quadrup