High telomerase activity is detected in nearly all human cancers but most human 
cells are devoid of telomerase activity. There is well-documented evidence that 
reactivation of telomerase occurs during cellular transformation. In humans, 
tumors can rely in reactivation of telomerase or originate in a telomerase 
positive stem/progenitor cell, or rely in alternative lengthening of telomeres, 
a telomerase-independent telomere-length maintenance mechanism. In this review, 
we will focus on the telomerase positive tumors. In this context, the recent 
findings that telomerase reverse transcriptase (TERT) promoter mutations 
represent the most common non-coding mutations in human cancer have flared up 
the long-standing discussion whether cancer originates from telomerase positive 
stem cells or telomerase reactivation is a final step in cellular 
transformation. Here, we will discuss the pros and cons of both concepts in the 
context of telomere length-dependent and telomere length-independent functions 
of telomerase. Together, these observations may provoke a re-evaluation of 
telomere and telomerase based therapies, both in telomerase inhibition for 
cancer therapy and telomerase activation for tissue regeneration and anti-ageing 
strategies.