Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating the stem cell pool throughout life. Self-renewal is division with maintenance of the undifferentiated state. This requires cell cycle control and often maintenance of multipotency or pluripotency, depending on the stem cell. Self-renewal programs involve networks that balance proto-oncogenes (promoting self-renewal), gate-keeping tumor suppressors (limiting self-renewal), and care-taking tumor suppressors (maintaining genomic integrity). These cell-intrinsic mechanisms are regulated by cell-extrinsic signals from the niche, the microenvironment that maintains stem cells and regulates their function in tissues. In response to changing tissue demands, stem cells undergo changes in cell cycle status and developmental potential over time, requiring different self-renewal programs at different stages of life. Reduced stem cell function and tissue regenerative capacity during aging are caused by changes in self-renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate self-renewal programs.