Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. They play a critical role in keeping genome stable and preventing premature aging diseases and the development of cancer. Characterizing mechanisms of telomere maintenance and understanding how their deregulation contributes to human diseases are therefore important for developing novel therapies. A key mechanism driving telomere maintenance and replicative immortality in cancer cells is telomere elongation by telomerase, and many emerging potential telomere-based therapies have focused on targeting telomerase components. By contrast, recent studies on telomere maintenance mechanism suggest that disrupting telomere stability by interfering with alternative mechanisms of telomere synthesis or protection may also yield new strategies for the treatment of cancer.