Abstract Mcm2 is a component of the DNA replication licensing complex that marks DNA replication origins during G1 of the cell cycle for use in the subsequent S-phase. It is expressed in stem/progenitor cells in a variety of regenerative tissues in mammals. Here, we have used the Mcm2 gene to develop a transgenic mouse in which somatic stem/progenitor cells can be genetically modified in the adult. In these mice, a tamoxifen-inducible form of Cre recombinase is integrated 3′ to the Mcm2 coding sequence and expressed via an internal ribosome entry site (IRES). Heterozygous Mcm2IRES-CreERT2/wild-type (wt) mice are phenotypically indistinguishable from wild-type at least through 1 year of age. In bigenic Mcm2IRES-CreERT2/wt; Z/EG reporter mice, tamoxifen-dependent enhanced green fluorescence protein expression is inducible in a wide variety of somatic stem cells and their progeny. However, in Mcm2IRES-CreERT2/IRES-CreERT2 homozygous embryos or mouse embryonic fibroblasts, Mcm2 is reduced to approximately one-third of wild-type levels. Despite the fact that these mice develop normally and are asymptomatic as young adults, life span is greatly reduced, with most surviving to only ∼10–12 weeks of age. They demonstrate severe deficiencies in the proliferative cell compartments of a variety of tissues, including the subventricular zone of the brain, muscle, and intestinal crypts. However, the immediate cause of death in most of these animals is cancer, where the majority develop lymphomas. These studies directly demonstrate that deficiencies in the function of the core DNA replication machinery that are compatible with development and survival nonetheless result in a chronic phenotype leading to stem cell deficiency in multiple tissues and cancer. Disclosure of potential conflicts of interest is found at the end of this article.