Regeneration of many cell types found in adult organs relies upon the presence of relatively small pools of undifferentiated stem cells. Initial studies that attempted to isolate stem cells and propagate them in vitro have been complemented by analysis of stem cells in their endogenous tissues where they are subject to a variety of regulatory cues. This has been facilitated by the advent of new methods for lineage tracing and genetic manipulation of stem cells and their associated niche cells. The picture that is emerging is that different stem cell populations utilize diverse processes to ensure maintenance of the stem cell pool accompanied by production of cells committed to regenerate differentiated cells.