Entry into and progression through mitosis are controlled by protein kinases and phosphatases, only some of which have been identified. When DNA is damaged, cells activate a checkpoint which blocks entry into mitosis and whose mechanism is little known. Cancer cells have weakened checkpoints, a major cause of their characteristic genomic instability. To develop novel approaches to cancer therapy, we wish to exploit this difference between normal and cancer cells. Therefore we are identifying kinases and phosphatases responsible for checkpoint control and for mitotic progression; studying their regulation using mutation and inhibitors, and identifying new drugs that can overcome the checkpoint for use in combination therapy with DNA-damaging agents.