Although telomerase, which maintains the ends of chromosomes, is down-regulated as cells differentiate leading to attrition of chromosomal termini and ultimate replicative senescence, it is up-regulated in most cancer cells which show no net loss of average telomere length. The mRNA level of the catalytic component of telomerase, hTERT, is the major determinant of telomerase activity but little is known about control of hTERT transcription. We propose mechanisms whereby cytosine methylation may alter the binding of activators such as c-Myc or repressors such as WT1 which interact with the hTERT gene regulatory region to modulate telomerase activity in aging cells and tumorigenesis. Mechanisms are also proposed for control of hTERT expression through changes in the collective binding of its transcription factors in aging and tumorigenic cells. Elucidation of telomerase regulation should facilitate advances in understanding age-related diseases such as cancer and in potential therapeutic modalities. © 2001 Harcourt Publishers Ltd.