DNA provides the blueprint for all living organisms. The simplicity of DNA double helix, combined with its enormous length, makes our living world of unlimited diversity and astounding beauty. At its most elementary level, every cell must accurately replicate its DNA once per cell division. Following the completion of DNA replication, each daughter cell must receive a full complement of the genome through accurate chromosome segregation. Defects in these processes lead to genome instabilities, including chromosomal rearrangements and aneuploidy that are prevalent in many diseases. Despite all that have been learned, cellular controls of DNA replication and chromosome segregation remain incompletely understood. The overarching goals of our research are to understand how these processes work and to develop new and powerful proteomics technology to detect genome instabilities that are prevalent in human diseases.