Mutations in DNA repair factors are increasingly recognized for having deleterious effects on hematopoiesis and increasing risk for developing hematopoietic malignancies (HMs). These genomically unstable cancers exhibit increases in somatic mutation rates as well as cases of large-scale chromosomal aberrations and translocations. In my thesis work, I investigated alterations in the homologous recombination (HR) DNA repair pathway, centered on the ATM-CHEK2-BRCA1 response to double strand breaks (DSBs). My work addresses the mechanisms of genomic instability that leads to an HM due to alterations in HR repair and effects on the cellular response to DNA damage and replication stress. The findings from my thesis work highlight the dual role that HR-associated factors play at stressed replication forks and implicate replication-mediated DNA damage in the etiology of genomic instability in hematopoietic cells. I investigated the mechanisms of genomic instability leading to recurrent Tcra/Myc-Pvt1 translocations in a T-cell leukemia model with aberrantly stabilized β-catenin. I show that DSBs in the Tcra site of the translocation are Rag-generated whereas the Myc-Pvt1 DSBs are not. I find that aberrant activation of β-catenin in thymocytes leads to a Tcf-1 mediated downregulation of HR-pathway member that promotes the retention of replication-mediated DSBs, providing the conditions for translocations to form. I also investigated a mouse model with hematopoietic-specific knockout (KO) of Brca1 that produces bone marrow failure and HMs with widespread chromosomal aberrations. My investigations into the mechanism of this genomic instability in the absence of this central HR factor implicate replication fork restart failures and the use of more error prone backup pathway for DSB repair, including non-homologous end joining (NHEJ) and alternative end joining (alt-EJ). Importantly, I show that bone marrow that is heterozygous for Brca1 also shows mild deficiencies at stressed replication forks and increased expression of NHEJ and alt-EJ factors. Finally, I investigated germline variants in the cell cycle regulator, CHEK2, for their contribution to increased risk for developing an HM. My work helps to identify two CHEK2 alleles, c.470C>T/p.I200T and c.1283C>T/p.S428P, as increasing the odds of developing an HM for patient carriers. Furthermore, I use a mouse model of the CHEK2 p.I200T allele and show that these mice develop leukocytosis, clonal hematopoiesis, and HMs at late stages. This suggest that variants in CHEK2 can alter the proliferation rates and somatic mutation rates in hematopoietic cells, contributing to genomic instability and outgrowth of bone marrow clones. Taken together, my studies highlight the dual role that HR factors play in repairing DSBs and in managing replication stress. I show how altered function can lead to failures of both replication fork protection and DSB repair, which act synergistically to increase genomic instability in these cells. These findings contribute additional context both to our understanding of current risks for carrying a mutation in these genome maintenance genes, and also opening up new therapeutic targets for treatment of HR-deficient HMs.