Stem cells are a promising source for regenerative medicine to cure a plethora of diseases that are currently treated based on either palliative or symptomatic relief or by preventing their onset and progression. Aging-associated degenerative changes in stem cells, stem cell niches, and signaling pathways bring a step by step decline in the regenerative and functional potential of tissues. Clinical studies and experiments on model organisms have pointed out checkpoints that aging will inevitably impose on stem cell aiming for transplantation and hence questions are raised about the age of the donor. In the following discourse, we review the fundamental molecular pathways that are implicated in stem cell aging and the current progress in tissue engineering and transplantation of each type of stem cells in regenerative medicine. We further focus on the consequences of stem cell aging on their clinical uses and the development of novel strategies to bypass those pitfalls and improve tissue replenishment.