Abstract: Homologous recombination (HR) is an essential DNA double strand break (DSB) repair pathway in vertebrates. The role of the b&barbelow;reast c&barbelow;ancer susceptibility gene 1&barbelow; (BRCA1) in the HR pathway has been clear for some time, although the relative contribution that this function makes in suppressing tumorigenesis has been elusive due to the plethora of functions that are assigned to the BRCA1 protein product. The results of the present study suggest that the critical, evolutionarily conserved function of BRCA1 in response to DSBs is in regulation of the HR pathway. Genetic analysis of a BRCA1-null derivative of the DT40 cell line indicates that over-expression of RAD51, the core eukaryotic recombinase, is capable of bypassing BRCA1 function in the assembly of RAD51 at DSBs, a critical event in HR mediated repair. This rescues both the sensitivity of BRCA1 cells to a variety of genotoxins and partially restores HR activity that is abrogated in the BRCA1-null DT40 background. Analysis of transcriptional micro-array data from BRCA1-positive tumors suggests that recombinase up-regulation is a common event during BRCA1-mediated tumorigenesis. Together with epistasis and cell-synchronization studies, these results support the conclusion that the HR pathway is the relevant deficiency underlying BRCA1 DNA damage sensitivity and also support a revised model of BRCA1 mediated tumorigenesis involving compensatory upregulation of the HR pathway in BRCA1-positive tumors. A related set of results indicates that the HR pathway is critical to the replication program in vertebrates. Previous observations lead to a model wherein loss of RAD51 function leads to the accumulation of chromosome breaks and terminal cell-cycle arrest. It was speculated that these breaks were derived from replicative failures during DNA synthesis. I find that the failure in replication is more pronounced following RAD51 depletion and that RAD51-null cells are incapable of completing even a single round of replication. RAD51 depletion leads to cessation of DNA synthesis and replication fork collapse. Collectively these results indicate that the HR pathway is more critical during replication that previous models held and suggest that replication stalling lesions that require HR for their resolution are commonly encountered by progressing replication forks.