While alterations to DNA underlie genome evolution and antibody diversification, genome instability drives many disorders, including cancer, developmental abnormalities, and neurodegeneration. DNA damage and other genome-threatening replication blocks are generally overcome by a number of DNA repair pathways. The choice of DNA repair pathways, specifically the reliance on error-prone vs. error-free is both intriguing and confounding. Moreover, the deregulation of repair pathway choice can trigger pathological processes. In this conference, we will discuss the delicate equilibrium of genome maintenance pathways, addressing how natural processes such as replication and transcription can threaten genome stability, how the genome can be altered in cancer, signatures of genome instability in human disease, and how cells control the inherent plasticity of their replication and repair machinery. We aim to bring together scientists from diverse fields who are interested in understanding the many processes impacting DNA metabolism and the molecular and biophysical principles that maintain the balance between genome stability and plasticity.