<p>While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.</p>