Hematopoietic reconstitution after transplantation relies on a small number of hematopoietic stem cells that selectively migrate from the bloodstream to the hematopoietic microenvironment. In the first phase of engraftment, an extreme proliferative demand causes a limited stem cell fraction and its progeny to divide continuously, showing a significant telomere shortening. When all hematopoietic compartments are fully reconstituted, progenitor cell replication stabilizes and the stem cell pool reverts to a quiescent state. In transplant recipients, the hematopoietic microenvironment and stem cell reservoir remain defective for a prolonged period. However, in most patients donor-derived polyclonal hemopoiesis results, and the system is not exhausted but is capable of sustained normal counts and eventually overcomes stressed conditions.