DNA damage, blocks to DNA replication, decatenation defects, and mitotic spindle perturbations all trigger “checkpoint” responses which delay cell cycle progression, promote repair, and protect genome integrity in all eukaryotes from yeasts to humans. The Chk1 protein kinase is a key regulator of multiple checkpoint responses in vertebrate cells, however the underlying biochemical mechanisms are poorly understood. We are using a combination of genetics and biochemistry in mice and cultured cells to address two principal questions: 1) How do checkpoints work at the molecular level, and 2) Are checkpoints required for the evolution of tumour cells during carcinogenesis and do they help them to survive exposure to radiation and genotoxic anti-cancer drugs? Our aim is to identify rational strategies through which pharmacological inhibition of checkpoints can be exploited for therapeutic purposes.