Abstract This application focuses on understanding the genetic basis of a recently recognized cancer-prone syndrome caused by long telomere length. It is driven by extended cellular longevity, a mechanism that is distinct from tumor suppressor- and oncogene-mediated familial cancer syndromes. Telomere length is constrained in the human population to a relatively narrow range and telomerase elongation is tightly regulated. Recent studies, from multiple lines of evidence from our group and others, have uncovered that genetically-determined short telomere length, at certain thresholds, is protective against most age-related malignancies. Exceptions include squamous cancers that arise in the setting of T cell immune exhaustion, and myelodysplastic syndrome and acute myeloid leukemia that arise in the setting of hematopoietic stem cell failure. These cancers occur at significantly higher rates among individuals with Mendelian short telomere syndromes. The relatively lower risk of other age-related malignancies in the short telomere syndromes has deep mechanistic underpinnings as short telomere length mediates cellular senescence and apoptosis, thus limiting cancer evolution in nearly all tumor-prone animal models. By contrast, there is emerging evidence that long telomere length is associated with significantly increased cancer risk in the human population with common variants in telomere genes increasing the risk for more than 28 malignancies. Our group recently reported on an autosomal dominant long telomere syndrome caused by heterozygous mutations in POT1. Haploinsufficiency of POT1 enhances telomerase elongation in vitro, and we found mediates ultra-long telomere length. POT1 mutation carriers with long telomeres had high cancer penetrance, near 100% by age 60, and were prone to multiple malignancies including melanoma, thyroid cancer, sarcoma, epithelial and hematologic malignancies. Alongside, they shared a predilection to high rates of clonal hematopoiesis, which