In neoplasia, telomere maintenance mechanisms (TMMs) can be prognostic and may direct therapy in the future. Two types of TMM, telomerase and recombination-based alternative lengthening of telomeres (ALT), result in four prognostic tumor groups when they occur individually, in combination, or in mutual absence. Correct designation of the TMM therefore requires an assessment of telomerase activity and for ALT telomere length distribution and ALT associated promyelocytic leukaemia protein (PML) bodies (APBs). The four groups are associated with differing prognoses that are dependent on the tumor type. As TMM inhibitors are developed, oncologists will require that pathologists determine the TMM, and the treatments will differ accordingly. Furthermore, any anti-TMM therapy administered has the potential to selectively change the TMM used by a tumor, necessitating reassessment of the therapeutic strategy. Herein, we review the telomere maintenance mechanisms, the current diagnostic measures and their utility as prognostic markers in the clinical setting.