Mammals maintain a species-specific telomere length to allow sufficient, but not unlimited, cell division throughout life, and thus a delicate balance between processes contributing to aging and cancer. However, the mechanism of how this length is determined is unclear. Telomeres in the house mouse, Mus musculus are about four times longer than those of its relative Mus spretus, which displays human-length telomeres. We found that a single amino acid change in the helicase ‘Regulator of telomer elongation 1’ (Rtel1) is responsible for the dramatic differences in telomer length between the two mouse species. This discovery enables generating an invaluable mouse model with human-size telomeres for studying the effects of telomere shortening on aging and cancer, which until now could not be modeled in the house mouse.