: Faithful DNA replication and repair of DNA damage is important for prevention of disease and birth defects. My thesis work utilized reverse and forward genetic approaches to identify novel genes involved in these processes. In one set of studies, I investigated the function of MCM9, a protein specific to multicellular eukaryotes that is related to subunits of the DNA replicative helicase. Utilizing multiple mouse disruption alleles, I have shown MCM9 is dispensable for DNA replication, however it has a role in germ-line stem cell maintenance and/or proliferation. Additionally, in the soma, Mcm9 mutation leads to increased cancer susceptibility, particularly hepatocellular carcinoma in males. The phenotypes of MCM9 mutant mice and cells suggest that MCM9 evolved a specialized but nonessential role in DNA replication or replication-linked quality-control mechanisms. In a second set of studies, I identified a hypomorphic allele of Fancm in a forward genetic screen for GIN mutations in mice. Fancm is a member of the Fanconi Anemia complementation group and facilitates repair of lesions at the DNA replication fork. Similar to Mcm9, Fancm is required for producing a normal germ-line stem cell pool and for tumor suppression in the soma. Together, these genetic studies underscore the importance of accurate DNA replication and repair of replication-associated damage in mammalian reproduction and cancer.