Oligonucleotide-based therapies have been under investigation for many years, and different antisense oligomers are being tested in clinical trials on patients with cancer and other diseases. Since telomerase reactivation has been defined as one of the six hallmarks of cancer because of the enzymes ability to provide tumor cells with unlimited proliferative potential, antisense-based approaches, aimed to inhibit the core enzyme components, could represent innovative anticancer therapies. Overall, available information indicates antisense-based strategies as powerful tools to inhibit telomerase and interfere with tumor cell proliferative potential. Specifically, cancer cell growth arrest was observed in several tumor models as a consequence of telomere shortening in the presence of prolonged telomerase inhibition. However, in other studies, antisense-based treatments caused rapid loss of tumor cell viability and induced apoptosis independently of telomere attrition. The results would suggest that telomerase inhibition affects tumor cell growth by mechanisms that are dependent as well as independent of the enzyme telomere elongating activity. However, the role of telomerase in tumorigenesis and tumor progression, beyond the classical mechanism of telomere lengthening, needs to be further investigated to provide a better rationale for the design and development of antitelomerase-based therapies in clinical oncology.