Summary: DNA nucleases play a key role in resolving stalled and collapsed replication forks, but the molecular events involved in these processes are not fully defined. This dissertation addresses how the DNA nuclease SNM1B plays critical roles in preventing replication-associated DNA damage. I demonstrate that SNM1B is not required for the initial detection of a stalled replication fork or for initiating early signaling events. I show that SNM1B is instrumental in stabilizing stalled replication forks by nucleolytically processing aberrant DNA structures at stalled and collapsed forks which allows for the recruitment of key DNA repair factors, FANCD2, BRCA1, and Rad51. Furthermore, I found that SNM1B plays a key role in preventing stalled and collapsed replication forks in unperturbed cells suggesting it is critical in responding to replication-associated DNA damage that occurs spontaneously during cellular proliferation. I also identified a residue within SNM1B that is critical for its localization to sites of stalled forks and established that SNM1B protein levels are modulated in the cell. Altogether, these findings illustrate that SNM1B has critical functions during the repair of replication-associated DNA damage, thereby ensuring successful replication of the genome and preventing potentially deleterious chromosomal aberrations.