DNA replication is a fundamental process in all organisms. Using single stranded DNA (ssDNA) as a template, DNA polymerase synthesizes new DNA to produce an exact copy of the genome. However, most DNA polymerases lack the ability to unwind the double stranded DNA (dsDNA) necessary to expose ssDNA [1]. Therefore, an additional DNA helicase is required to initiate DNA replication by unwinding dsDNA and exposure of ssDNA as a template. In eukaryotes, genetic and biochemical assays have shown the MCM (minichromosome maintenance) family of proteins functions in a hexameric complex as the genomic DNA replication helicase [2]. MCMs have been well studied through in vitro biochemistry, cells in culture, and simple model organisms including S. cerevisiea and Xenopus laevis. These experimentally tractable systems have shown that misrelated or dysfunctional MCMs have deleterious consequences, especially genomic instability (GIN). However, there are still several major unresolved issues that need to be addressed. (1) The "MCM paradox" described that the MCMs are in excess of the number of origins. What is the function of these excess MCMs, and how does it relate to cells and animals? (2) The "MCM puzzle" indicates that mini-MCM complexes exist, but their functions are still unclear (3) Very little is known about the function of the MCM helicase with respect to the health of whole animals. To accomplish these issues and explore the relationship between MCMs and disease, I generated mice deficient in MCMs as a model of in vivo disease in this thesis. The mice which carry 50% reduction of Mcm2, 3, 4, 6, and 7 is phenotypically identical to wild-type at least through 1 year of age. Further reduction of Mcms to 70% causes several detrimental phenotypes, including embryonic lethality, growth retardation, genomic instability, and cancer susceptibility. Most importantly, the reduction of MCM3 rescues most of the detrimental phenotypes in other MCM deficient mice, suggesting a unique function of MCM3. Highly similar to in vitro results, I showed that the MCM3/5 dimer inhibits the MCM2-7 complex from binding chromatin and hinders cell cycle. I also discovered that the Mcm4Chaos3 mutation induces a pan-downregulation of Mcm2-7 post-transcriptionally. The pan-down regulation of Mcm2-7 is a self-preservation mechanism because it reduces MCM3 levels that block the recruitment of chromatin bound MCM2-7. Finally, I identified that Mcm hypomorphic mice possess a unique gender bias phenotype. The male animals are more resistant to MCM insufficiency due to a testosterone protective effect. In summary, this dissertation explores the function of the excess MCMs in aspects of cell cycle and in whole animals. It builds understanding about the regulation of MCMs with emphasis upon cancer formation as a result of MCM deficiency. The MCM hypomorphic mice also reveal a post-transcriptional regulation of Mcms that responded to helicase complex instability or insufficiency. The unique negative function of the MCM3/5 dimer overturns the current theory that the MCM2-7 heterohexamer is the only type of replication helicase that forms.