The small intestinal epithelium has enormous capacity for self-renewal, replacing itself every 3 to 5 days. The cellular basis for this regenerative potential has long been accepted to reside in rare, slowly cycling and multipotent intestinal stem cells (ISCs), though functionally validated markers remained elusive for over three decades. Recently, using lineage-tracing methods, the first functionally validated ISC marker, Lgr5, was identified. Surprisingly, each intestinal crypt contains multiple Lgr5-expressing cells at its base that are rapidly cycling and highly sensitive to injury. In contrast, mTert-expressing cells, present as single cells located predominantly at the “+4” crypt position, function as quiescent, long-lived and multipotent ISCs. While rapidly cycling ISCs play a major role during daily homeostasis, slowly cycling ISCs are “activated” upon intestinal injury and underlie the regenerative response by restoring the rapidly cycling population. Despite these important advances, little is known about the mechanisms controlling ISC activation or how aging affects this process.