To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm−/− mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy. Display omitted ► Telomerase reactivation following genomic instability promotes invasiveness ► Telomerase inhibition leads to cell death and eventual ALT-dependent resistance ► ALT+ cells upregulate PGC axis to rescue mitochondrial dysfunction and reactive oxygen species (ROS) ► Mitochondria/ROS fitness can be targeted to enhance antitelomerase therapy Decreasing telomerase activity initially slows tumor growth in a mouse model of lymphoma, but eventually growth resumes as resistant cells emerge. These cells display aberrant mitochondrial function and are sensitive to PGC-1β inhibition, offering a new target for enhancing the effectiveness of antitelomerase therapy.