Telomerase is an attractive target for anti-cancer therapeutics due to its requirement for cellular immortalization and expression in greater than 85% of human neoplasms. Though initially promising, strategies that inhibit telomerase with either small molecules or antisense oligonucleotides have a major limitation, namely the lag time required for telomere shortening before cellular effects are attained. As alternative approaches, immunotherapy and gene therapy have been tailored to exploit, rather than antagonize telomerase expression and/or activity. Immunotherapy requires the presence of the catalytic subunit of telomerase, hTERT, to elicit an immune response directed towards hTERT peptide-presenting cells. hTERT promoter-driven gene therapy and mutant telomerase RNA (hTR) gene therapy depend on the innate telomerase activity of cancer cells to drive the expression of pro-apoptotic genes and to synthesize mutated DNA sequences onto telomeres, respectively. In addition, we will discuss telomestatin, a G-quadruplex binding ligand that may exert anti-proliferative effects independently of telomere shortening. In this review, the progress, advantages, and limitations of these strategies in the ongoing effort to develop clinically relevant telomerase-based cancer therapeutics will be examined.