Hematopoietic stem cells (HSC) have a finite proliferative lifespan, based upon the limited number of times they can be serially transplanted in mice. Telomeres have been shown to shorten during the division of many normal somatic cells in humans, and the attrition of telomeres has been shown to ultimately cause replicative senescence in vitro for a number of different human cell strains. Whereas most human cell types have little to no detectable levels of telomerase activity, hematopoietic cells, including HSC, express low to moderate levels of telomerase, and yet telomeres shorten considerably during replicative aging of these cells. Here we consider the role telomerase may play in the hematopoietic system as well as the effect that over-expression of telomerase reverse transcriptase may have on the replicative capacity of hematopoietic stem cells during transplantation.