Over the past two decades, it has become increasingly apparent that telomerase-mediated telomere maintenance plays a crucial role in hematopoiesis. Supporting evidence is underscored by recent findings of mutations in genes involved in telomerase-mediated telomere maintenance that contribute to the pathogenesis of bone marrow failure syndromes. More recently described telomere-independent functions of telomerase are also likely to contribute to both normal hematopoiesis and hematologic diseases. The high levels of telomerase detected in aggressive leukemias have fueled fervent investigation into diverse approaches to targeting telomerase in hematologic malignancies. Successful preclinical investigations that employed genetic strategies, oligonucleotides, small-molecule inhibitors and immunotherapy have resulted in a rapid translation to clinical trials. Further investigation of telomere-independent functions of telomerase and detailed preclinical studies of telomerase inhibition in both normal and malignant hematopoiesis will be invaluable for refining treatments to effectively and safely exploit telomerase as a therapeutic target in hematologic malignancies.