Telomeres are essential for protecting chromosome ends from genome instability. They consist of repetitive DNA sequences and associated proteins that form a protective structure, preventing the DNA damage response (DDR) from recognizing them as breaks. When telomeres are shortened or damaged, they can lead to chromosome fusions, genome instability, and cancer. The shelterin complex, composed of six proteins including TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, is crucial for telomere protection and length regulation. TRF1 and TRF2 are involved in maintaining telomere structure and preventing DDR activation, while POT1 binds to the telomeric overhang and helps in telomere protection. Telomerase, which adds telomeric repeats, is essential for maintaining telomere length in stem cells and germ cells. However, telomerase overactivity can lead to cellular immortality without transformation. Telomere dysfunction can result in genome instability, as seen in diseases like Dyskeratosis Congenita and Idiopathic Pulmonary Fibrosis. The DDR machinery, including ATM and ATR, is involved in detecting and repairing telomere damage, but dysfunctional telomeres can be recognized as DNA breaks, leading to chromosomal fusions and breakage-fusion-bridge cycles. Telomere dysfunction is a key factor in cancer development and aging. Understanding the complex interactions between telomeres, shelterin, and DDR pathways is crucial for developing therapies targeting telomere-related diseases.Telomeres are essential for protecting chromosome ends from genome instability. They consist of repetitive DNA sequences and associated proteins that form a protective structure, preventing the DNA damage response (DDR) from recognizing them as breaks. When telomeres are shortened or damaged, they can lead to chromosome fusions, genome instability, and cancer. The shelterin complex, composed of six proteins including TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, is crucial for telomere protection and length regulation. TRF1 and TRF2 are involved in maintaining telomere structure and preventing DDR activation, while POT1 binds to the telomeric overhang and helps in telomere protection. Telomerase, which adds telomeric repeats, is essential for maintaining telomere length in stem cells and germ cells. However, telomerase overactivity can lead to cellular immortality without transformation. Telomere dysfunction can result in genome instability, as seen in diseases like Dyskeratosis Congenita and Idiopathic Pulmonary Fibrosis. The DDR machinery, including ATM and ATR, is involved in detecting and repairing telomere damage, but dysfunctional telomeres can be recognized as DNA breaks, leading to chromosomal fusions and breakage-fusion-bridge cycles. Telomere dysfunction is a key factor in cancer development and aging. Understanding the complex interactions between telomeres, shelterin, and DDR pathways is crucial for developing therapies targeting telomere-related diseases.