Stem/progenitor cells ensure tissue and organism homeostasis and might represent a frequent target of transformation. Although these cells are potentially immortal, their life span is restrained by signaling pathways (p19-p53; p16-Rb) that are activated by DNA damage (telomere dysfunction, environmental stresses) and lead to senescence or apoptosis. Execution of these checkpoint programs might lead to stem cell depletion and organism aging, while their inactivation contributes to tumor formation.