Most tissues undergo significant expansion during postnatal life, as well as a lifelong cellular turnover to compensate for cell loss. What is the identity of cells that give rise to newly differentiated cells? This fundamental yet understudied question is now attracting the attention of biologists and clinicians, triggered by reports that essentially every tissue can be replenished and repaired by multipotent adult stem cells. The identification of the "cell of origin" for a given tissue is essential for understanding its dynamics during adult life, and may have important therapeutic implications for both degenerative and neoplastic diseases. In this commentary, we briefly outline classic and current views on the question of the cell of origin. We also describe a general method that we have recently developed for addressing this issue, and its first application for the study of pancreatic beta cells.