Hematopoietic stem cells (HSCs) provide the basis for the enormous regenerative capacity of the hematopoietic system. Despite the need for a lifelong production of blood cells, replicative exhaustion seems to affect the HSC pool. Erosion of telomeres, protective structures at the ends of eukaryotic chromosomes, limits the replicative life span of most somatic cells. The expression of telomerase, the enzyme synthesizing telomeres de novo, is restricted to highly proliferative cells like germ line cells and tumor cells. Adult stem cells such as HSCs still exhibit telomerase activity to a certain level. Here, the telomerase activity does not prevent telomere shortening, suggesting a restriction of the proliferative capacity of HSCs. In this review, we discuss the relevance of telomere maintenance, potential functions of telomerase, and possible clinical applications of telomere manipulation in the hematopoietic stem cell compartment. Furthermore, we discuss new insights affecting the aging of the hematopoietic stem cell pool besides replicative exhaustion.