One of the unique characteristics acquired by cancer cells is uncontrolled cell proliferation, attributed to upregulated telomerase expression that maintains telomere length. Telomeres are specialized repeat arrays of sequences present at chromosome termini. Telomere length provides stability and prevents chromosomal fusions and protects from other degradation. Telomeres are maintained by a specialized ribo-nucleoprotein complex called Telomerase, which is over-expressed in 90% of cancer cells and absent or undetectable in normal somatic cells. The longer the telomere length, the more the protection by Shelterin complex protein that hides the telomere to be recognized as DNA damage. So, telomere length provides proliferative advantage to cells and cancer cells proliferate uncontrollably. Normal somatic cells lack telomerase and due to which the telomere length gets reduced at every cell division which is called end replication problem. One of the earlier ideas of cancer therapeutics is to target telomerase and inducing “end replication problem”. If the telomerase enzyme is blocked by any means, the telomere length gets reduced and induces a DNA damage signal and in turn, signals for cell death. This chapter though not very comprehensive, will reveal the biology of telomeres and strategies for targeting telomerase by nucleic acid-based, peptide based, and natural phytochemical-based approaches that have been explored so far to evaluate the telomerase as a target for cancer therapies.