Studies to uncover genes regulating stem cells usually adopt one of two distinct lines of investigation: forward genetics and reverse genetics approaches. The forward genetics approach proceeds from measurable phenotypic differences to genetic polymorphism and, as the name implies, the path of investigation is reversed using reverse genetics. The number of newly discovered loci responsible for stem cell–specific phenotypes and functioning is increasing at a rapid rate owing to the success of both approaches. These loci regulate stem cells by intrinsic (cell autonomous) and/or extrinsic mechanisms and dictate stem-cell fate decisions. During the aging process, stem cells undergo both quantitative and qualitative changes, which are hypothesized to affect both the rate of aging and the longevity of an organism.