Precise duplication of the genetic material and equal distribution to daughter cells are essential for maintaining genome integrity. Progression through the cell cycle is tightly regulated by a family of cyclin-dependent kinases (Cdk), which associate with respective cyclin subunits. In normal cells, cyclin E accumulates at the G1/S transition, and promotes DNA duplication by binding to and activating Cdk2. However, in different human cancers, cyclin E is frequently found to be overexpressed or deregulated, and is associated with tumor development and aggressiveness. Using a combination of cellular, molecular, biochemical, and genomic approaches, we are studying the mechanisms by which cyclin E/Cdk2 activity controls proper DNA replication in normal cells, and how deregulation of cyclin E perturbs S phase progression and leads to genomic instability in cancer.